US9221914B2 - Agents targeting CD138 and uses thereof - Google Patents

Agents targeting CD138 and uses thereof Download PDF

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US9221914B2
US9221914B2 US12/342,285 US34228508A US9221914B2 US 9221914 B2 US9221914 B2 US 9221914B2 US 34228508 A US34228508 A US 34228508A US 9221914 B2 US9221914 B2 US 9221914B2
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antibody
seq
sequence
nbt062
targeting
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US20090175863A1 (en
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Elmar Kraus
Christoph Bruecher
Benjamin Daelken
Matthias Germer
Steffen Zeng
Frank Osterroth
Christoph Uherek
Silke Aigner
Gregor Schulz
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Biotest AG
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/2896Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants against molecules with a "CD"-designation, not provided for elsewhere
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    • C07ORGANIC CHEMISTRY
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    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K39/395Antibodies; Immunoglobulins; Immune serum, e.g. antilymphocytic serum
    • A61K47/48384
    • A61K47/48561
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6801Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
    • A61K47/6803Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
    • A61K47/68033Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a maytansine
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K47/00Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
    • A61K47/50Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
    • A61K47/51Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
    • A61K47/68Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
    • A61K47/6835Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site
    • A61K47/6849Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment the modifying agent being an antibody or an immunoglobulin bearing at least one antigen-binding site the antibody targeting a receptor, a cell surface antigen or a cell surface determinant
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61PSPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00Antineoplastic agents
    • A61P35/02Antineoplastic agents specific for leukemia
    • CCHEMISTRY; METALLURGY
    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K16/00Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies
    • C07K16/18Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans
    • C07K16/28Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants
    • C07K16/30Immunoglobulins [IGs], e.g. monoclonal or polyclonal antibodies against material from animals or humans against receptors, cell surface antigens or cell surface determinants from tumour cells
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/505Medicinal preparations containing antigens or antibodies comprising antibodies
    • AHUMAN NECESSITIES
    • A61MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61KPREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K39/00Medicinal preparations containing antigens or antibodies
    • A61K2039/545Medicinal preparations containing antigens or antibodies characterised by the dose, timing or administration schedule
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/10Immunoglobulins specific features characterized by their source of isolation or production
    • C07K2317/14Specific host cells or culture conditions, e.g. components, pH or temperature
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/20Immunoglobulins specific features characterized by taxonomic origin
    • C07K2317/24Immunoglobulins specific features characterized by taxonomic origin containing regions, domains or residues from different species, e.g. chimeric, humanized or veneered
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/30Immunoglobulins specific features characterized by aspects of specificity or valency
    • C07K2317/34Identification of a linear epitope shorter than 20 amino acid residues or of a conformational epitope defined by amino acid residues
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    • C07ORGANIC CHEMISTRY
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    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/51Complete heavy chain or Fd fragment, i.e. VH + CH1
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    • C07ORGANIC CHEMISTRY
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    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/50Immunoglobulins specific features characterized by immunoglobulin fragments
    • C07K2317/56Immunoglobulins specific features characterized by immunoglobulin fragments variable (Fv) region, i.e. VH and/or VL
    • C07K2317/565Complementarity determining region [CDR]
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    • C07ORGANIC CHEMISTRY
    • C07KPEPTIDES
    • C07K2317/00Immunoglobulins specific features
    • C07K2317/90Immunoglobulins specific features characterized by (pharmaco)kinetic aspects or by stability of the immunoglobulin
    • C07K2317/92Affinity (KD), association rate (Ka), dissociation rate (Kd) or EC50 value

Definitions

  • the present invention relates to improved targeting agents for the antigen CD138 as well as compositions comprising the targeting agent and methods employing them.
  • CD138 which acts as a receptor for the extracellular matrix, is overexpressed on multiple myeloma (MM) cells and has been shown to influence MM cell development and/or proliferation. CD138 is also expressed on cells of ovarian carcinoma, kidney carcinoma, gall bladder carcinoma, breast carcinoma, prostate cancer, lung cancer, colon carcinoma cells and cells of Hodgkin's and non-Hodgkin's lymphomas, chronic lymphocytic leukemia (CLL) to name just a few.
  • MM myeloma
  • a targeting agent in particular a targeting antibody based on B-B4 that is devoid of certain properties and/or functions associated with B-B4.
  • Such a targeting antibody may comprise one or more antibody regions of a human antibody.
  • a chimerized antibody based on B-B4 that binds CD138 as effectively as B-B4 but can be administered to humans without significant side effects.
  • a targeting agent having binding affinity that exceeds the binding affinity of B-B4.
  • B-B4 based targeting agent that shows one or more advantageous properties relative to its murine counterpart. Those properties include improved antigen binding, in particular of CD138 expressing tumor cells and cells accessory thereto or more homogenous binding.
  • the present invention is directed at a method for homogenous binding to CD138 comprising:
  • the present invention is also directed at an isolated polypeptide comprising an amino acid sequence of an immunoglobulin heavy chain or part thereof, wherein said immunoglobulin heavy chain or part thereof has at least 70%, at least 80%, at least 90%, at least 95% or at least 98% sequence identity with SEQ ID NO:1, wherein a targeting agent comprising said immunoglobulin heavy chain or part thereof targets CD138.
  • Said immunoglobulin heavy chain or part thereof may have at least 80%, at least 85%, at least 90%, at least 95% sequence identity with residues 31 to 35, residues 51 to 68 and residues 99 to 111 of SEQ ID NO:1 and said targeting agent may be an engineered targeting antibody.
  • a constant region of said immunoglobulin heavy chain or said part thereof may be an IgG4 isotype constant region.
  • Said targeting agent may be a mouse human chimeric antibody.
  • Said targeting agent or engineered targeting antibody may be a humanized antibody.
  • the isolated polypeptide may further comprise an amino acid sequence of an immunoglobulin light chain or part thereof, wherein said immunoglobulin light chain or part thereof may have at least 70%, at least 80%, at least 90%, at least 95% or least 98% sequence identity with SEQ ID NO:2.
  • the isolated polypeptide may further comprise an amino acid sequence of an immunoglobulin light chain or part thereof, wherein said immunoglobulin light chain or part thereof has at least 75%, at least 85%, at least 95% or at least 97% sequence identity with residues 24 to 34, residues 50 to 56 and residues 89 to 97 of SEQ ID NO:2.
  • Said immunoglobulin heavy chain may be identical to the sequence of SEQ ID NO:1.
  • Said immunoglobulin light chain may be identical to the sequence of SEQ ID NO:2.
  • the present invention is also directed at an engineered targeting antibody which recognizes CD138 comprising
  • an antigen binding region against CD138 wherein said antigen binding region is of a non-human antibody
  • Said further antibody region may be at least one constant region comprising a heavy chain constant region or a part thereof that is of a human antibody, and wherein said engineered antibody is of an IgG4 isotype.
  • Said engineered targeting antibody may be a chimeric antibody and said non-human antibody may be B-B4.
  • Said engineered targeting antibody may be a humanized antibody and said non-human antibody may be B-B4.
  • Said heavy chain may have at least 70%, at least 80%, at least 90%, at least 95% or at least 98% sequence identity with SEQ ID NO:1.
  • Said engineered targeting antibody may comprise at least one light chain, wherein said light chain has at least 70%, at least 80%, at least 90%, at least 95% or at least 98% sequence identity with SEQ ID NO:2.
  • Said heavy chain may have at least 80%, at least 85%, at least 90%, at least 95% or 100% sequence identity with residues 31 to 35, residues 51 to 68 and/or residues 99 to 111 of SEQ ID NO:1.
  • Said heavy chain may have at least 75%, at least 85%, at least 95%, at least 97% or 100% sequence identity with residues 24 to 34, residues 50 to 56 and/or residues 89 to 97 of SEQ ID NO:2.
  • the further antibody region may comprise:
  • Said further antibody region may be a constant heavy region of a human antibody.
  • Said engineered targeting antibody may bind CD138 with a targeting variation of less than 150%, 140%, 130%, 120%, 110%, 100%, 90%, 80%, 70%, 60% or 50%.
  • Said heavy chain may have at least 70%, at least 80%, at least 90%, at least 95% or at least 98% sequence identity with SEQ ID NO:1.
  • Said engineered targeting antibody may comprise at least one light chain, wherein said light chain has at least 70%, at least 80%, at least 90%, at least 95% or at least 98% sequence identity with SEQ ID NO:2.
  • Said heavy chain may have at least 80%, at least 85%, at least 90%, at least 95% sequence identity with residues 31 to 35, residues 51 to 68 and residues 99 to 111 of SEQ ID NO:1.
  • Said heavy chain may have at least 75%, at least 85%, at least 95% or at least 97% sequence identity with residues 24 to 34, residues 50 to 56 and residues 89 to 97 of SEQ ID NO:2.
  • the present invention is also directed at a pharmaceutical composition
  • a pharmaceutical composition comprising or consisting essentially of the engineered targeting antibody and a pharmaceutically acceptable carrier.
  • a hybridoma which produces the engineered targeting is also part of the present invention.
  • the present invention also includes an antibody based assay comprising the engineered targeting antibody.
  • the present invention provides an engineered targeting antibody for use in medicine, wherein the engineered targeting antibody comprises:
  • the engineered targeting antibody is for use in a treatment targeting tumor cells.
  • the present invention also provides the use of an engineered targeting antibody for the manufacture of a medicament for targeting tumor cells wherein the engineered targeting antibody comprises:
  • the engineered targeting antibody is to be administered to an individual with CD138 expressing cells. Further, the engineered targeting antibody is capable of homogenously binding CD138 expressed on said CD138 expressing cells.
  • FIG. 1 provides a schematic representation of nBT062 having effector molecules attached.
  • FIG. 2 is a chemical representation of BT062.
  • FIG. 3 shows the conversion of ansamitocin P-3 to maytansinol (stereochemistry is omitted for simplicity).
  • FIG. 4 shows a representative synthesis scheme of DM4.
  • FIG. 5 is a schematic representation of an antibody conjugation (nBT062 to DM4).
  • FIG. 6 shows an analysis of the binding of nBT062-SPDB-DM4, nBT062-SPP-DM1, nBT062-SMCC-DM1 and nBT062 antibody to OPM-2 cells. Different concentrations of nBT062 and conjugates were given to the cells and mean fluorescence was measured by FACS analysis.
  • FIG. 7 (A)-(D) depict in vitro cytotoxicity of nBT062-DMx conjugates towards MOLP-8 (CD138 + ) and BJAB (CD138 ⁇ ) cells.
  • the cells were cultured in flat bottom plates and incubated with the indicated concentrations of immunoconjugates for 5 days. WST reagent was added for further 3 hours to assess cell viability.
  • cytotoxic activity of nBT062-SPDB-DM4 was analyzed in the presence or absence of blocking antibody (1 ⁇ M nBT062).
  • FIG. 8 shows tumor volumes for individual mice treated with (A) PBS, (B) nBT062 antibody, (C) free DM4 or (D) non-targeting conjugate huC242-DM4 over time (days) post-inoculation with MOLP-8 tumor cells.
  • FIG. 9 shows tumor volumes for individual mice treated with (A) PBS, (B) nBT062-SPDB-DM4, (C) B-B4-SPP-DM1 or (D) nBT062-SPP-DM1 over time (days) post-inoculation with MOLP-8 tumor cells.
  • FIG. 10 depicts mean tumor volume (+/ ⁇ SD) of MOLP-8 human multiple myeloma xenografts in CB.17 SCID mice over time (days) post-inoculation.
  • FIGS. 11A and B show the anti-tumor activity of nBT062-DMx against CD138 + MOLP-8 tumor cells in a bulky MOLP-8 tumor model in SCID mice. Tumor volume is given as mean (+/ ⁇ SD) for each group.
  • the present invention relates to targeting agents, in particular CD138 targeting antibodies, more in particular engineered CD138 targeting antibodies.
  • Immunoconjugates comprising said targeting agents allow the delivery of the effector molecule(s) to target sites and the site specific release of effector(s) molecule in, at or near target cells, tissues and organs.
  • the effector molecules may be activated by cleavage/dissociation from the targeting agent portion of the immunoconjugate at the target site.
  • the antibodies according to the present invention and/or immunoconjugates comprising the same may be administered to a subject in need of therapeutic treatment or to cells isolated from such a subject in need of therapeutic treatment.
  • the effector molecule or molecules may be released from the immunoconjugate by cleavage/dissociation in, at or close to the target cell, tissue or organ.
  • the antibody nBT062 is employed in an chromographic assay. Formalin fixed, paraffin embedded tissue of a patient are provided. The antibody nBT062 is added as a primary antibody and surface expressed CD138 of the tissue binds the antibody. A detecting antibody is added to bind nBT062. In a final step, this binding of the detecting antibody, which comprises a chromogen is determined.
  • the antibody nBT062 is used identify human plasmocytes among hemopoietic cells and thus allows diagnosis of a variety of hematological malignancies. The method also allows one to follow the progress of certain carcinomas. A reduction of unspecific detection due to a reduced cross reactivity with Fc receptors is observed when nBT062 is employed as opposed to its murine counterpart.
  • the nBT062 antibody and an immunoconjugate that comprises the antibody nBT062 and at least one highly cytotoxic drug or an immunotoxin as an effector molecule are provided and administered to a patient with cancer.
  • an effective amount of nBT062 shields CD138 expressing non-tumor cells from a therapeutically effective amount of the immunoconjugate that is later administered intravenously to a patient so that it concentrates in the cancerous cells.
  • the effector molecule or molecules are released from the antibody target by an external means to induce cell death or continuous cell cycle arrest in the cancer cells.
  • CD138 or syndecan-1 (also described as SYND1; SYNDECAN; SDC; SCD1; CD138 ANTIGEN, SwissProt accession number: P18827 human) is a membrane glycoprotein that was originally described to be present on cells of epithelial origin, and subsequently found on hematopoietic cells (Sanderson, 1989).
  • CD138 has a long extracellular domain that binds to soluble molecules (e.g., the growth factors EGF, FGF, HGF) and to insoluble molecules (e.g., to the extracellular matrix components collagen and fibronectin) through heparan sulfate chains (Langford, 1998; Yang, 2007) and acts as a receptor for the extracellular matrix.
  • soluble molecules e.g., the growth factors EGF, FGF, HGF
  • insoluble molecules e.g., to the extracellular matrix components collagen and fibronectin
  • CD138 also mediates cell to cell adhesion through heparin-binding molecules expressed by adherent cells. It has been shown that CD138 has a role as a co-receptor for growth factors of myeloma cells (Bisping, 2006). Studies of plasma cell differentiation showed that CD138 must also be considered as a differentiation antigen (Bataille, 2006).
  • CD138 is highly expressed on the majority of MM cells, ovarian carcinoma, kidney carcinoma, gall bladder carcinoma, breast carcinoma, prostate cancer, lung cancer, colon carcinoma cells and cells of Hodgkin's and non-Hodgkin's lymphomas, chronic lymphocytic leukemia (CLL) (Horvathova, 1995), acute lymphoblastic leukemia (ALL), acute myeloblastic leukemia (AML) (Seftalioglu, 2003 (a); Seftalioglu, 2003 (b)), solid tissue sarcomas, colon carcinomas as well as other hematologic malignancies and solid tumors that express CD138 (Carbone et al., 1999; Sebestyen et al., 1999; Han et al., 2004; Charnaux et al., 2004; O'Connell et al., 2004; Orosz and Kopper, 2001).
  • CD138 Carbone et al., 1999; Sebestyen et al., 1999; Han e
  • cancers that have been shown to be positive for CD138 expression are many ovarian adenocarcinomas, transitional cell bladder carcinomas, kidney clear cell carcinomas, squamous cell lung carcinomas; breast carcinomas and uterine cancers (see, for example, Davies et al., 2004; Barbareschi et al., 2003; Mennerich et al., 2004; Anttonen et al., 2001; Wijdenes, 2002).
  • CD138 expression is restricted to plasma cells (Wijdenes, 1996; Chilosi, 1999) and CD138 is not expressed on peripheral blood lymphocytes, monocytes, granulocytes, and red blood cells.
  • CD34 + stem and progenitor cells do not express CD138 and anti-CD138 mAbs do not affect the number of colony forming units in hematopoietic stem cell cultures (Wijdenes, 1996).
  • CD138 is mainly expressed on simple and stratified epithelia within the lung, liver, skin, kidney and gut. Only a weak staining was seen on endothelial cells (Bernfield, 1992; Vooijs, 1996). It has been reported that CD138 exists in polymorphic forms in human lymphoma cells (Gattei, 1999).
  • B-B4, BC/B-B4, B-B2, DL-101, 1 D4, MI15, 1.BB.210, 2Q1484, 5F7, 104-9, 281-2 in particular B-B4 have been reported to be specific to CD138.
  • B-B4, 1D4 and MI15 recognized both the intact molecule and the core protein of CD138 and were shown to recognize either the same or closely related epitopes (Gattei, 1999).
  • Previous studies reported that B-B4 did not recognize soluble CD138, but only CD138 in membrane bound form (Wijdenes, 2002).
  • B-B4 a murine IgG1 mAb, binds to a linear epitope between residues 90-95 of the core protein on human syndecan-1 (CD138) (Wijdenes, 1996; Dore, 1998). Consistent with the expression pattern of CD138, B-B4 was shown to strongly react with plasma cell line RPMI8226, but not to react with endothelial cells. Also consistent with the expression pattern of CD138, B-B4 also reacted with epithelial cells lines A431 (keratinocyte derived) and HepG2 (hepatocyte derived). An immunotoxin B-B4-saporin was also highly toxic towards the plasma cell line RPMI8226, in fact considerably more toxic than free saporin.
  • B-B4-saporin showed only toxicity towards cell line A431, although in a clonogenic assay B-B4 saporin showed no inhibitory effect on the outgrowth of A431 cells (Vooijs, 1996).
  • Other researchers reported lack of specificity of MM-associated antigens against tumors (Couturier, 1999).
  • an antibody “consisting essentially of” certain components means in the context of the present invention that the antibody consists of the specified components and any additional materials or components that do not materially affect the basic characteristics of the antibody.
  • tumor cell to include cancer cells as well as pre-cancerous cells which may or may not form part of a solid tumor.
  • a “targeting agent” according to the present invention is able to associate with a molecule expressed by a target cell and includes peptides and non-peptides.
  • targeting agents according to the present invention include targeting antibodies and non-immunoglobulin targeting molecules, which may be based on non-immunoglobulin proteins, including, but not limited to, AFFILIN® molecules, ANTICALINS® and AFFIBODIES®.
  • Non-immunoglobulin targeting molecules also include non-peptidic targeting molecules such as targeting DNA and RNA oligonucleotides (aptamers), but also physiological ligands, in particular ligands of the antigen in question, such as CD138.
  • a “targeting antibody” according to the present invention is or is based on a natural antibody or is produced synthetically or by genetic engineering and binds to an antigen on a cell or cells (target cell(s)) of interest.
  • a targeting antibody according to the present invention includes a monoclonal antibody, a polyclonal antibody, a multispecific antibody (for example, a bispecific antibody), or an antibody fragment.
  • the targeting antibody may be engineered to, for example, improve its affinity to the target cells (Ross, 2003) or diminish its immunogenicity.
  • the targeting antibody may be attached to a liposomal formulation including effector molecules (Carter, 2003).
  • An antibody fragment comprises a portion of an intact antibody, preferably the antigen binding or variable region of the intact antibody.
  • antibody fragments according to the present invention include Fab, Fab′, F(ab′) 2 , and Fv fragments, but also diabodies; domain antibodies (dAb) (Ward, 1989; U.S. Pat. No. 6,005,079); linear antibodies; single-chain antibody molecules; and multispecific antibodies formed from antibody fragments.
  • a single chain variable fragment antibody scFv
  • the heavy and light chains VH and VL
  • VH and VL can be linked by a short amino acid linker having, for example, the sequence (glycine 4 serine) n , which has sufficient flexibility to allow the two domains to assemble a functional antigen binding pocket. Addition of various signal sequences may allow for more precise targeting of the targeting antibody.
  • variable regions for constructing the scFv can, if a mAb against a target of interest is available, be obtained by RT-PCR which clones out the variable regions from mRNA extracted from the parent hybridoma. Alternatively, the scFv can be generated de novo by phage display technology (Smith, 2001).
  • the term “functional fragment”, when used in reference to a targeting antibody, is intended to refer to a portion of the targeting antibody which is capable of specifically binding an antigen that is specifically bound by the antibody reference is made to.
  • a bispecific antibody according to the present invention may, for example, have at least one arm that is reactive against a target tissue and one arm that is reactive against a linker moiety (United States Patent Publication 20020006379).
  • a bispecific antibody according to the present invention may also bind to more than one antigen on a target cell (Carter, 2003).
  • An antibody according to the present invention may be modified by, for example, introducing cystein residues to introduce thiol groups (Olafsen, 2004).
  • the targeting antibody may be derived from any source and may be, but is not limited to, a camel antibody, a murine antibody, a chimeric human/mouse antibody or a chimeric human/monkey antibody, in particular, a chimeric human/mouse antibody such as nBT062.
  • Humanized antibodies are antibodies that contain sequences derived from a human-antibody and from a non-human antibody and are also within the scope of the present invention. Suitable methods for humanizing antibodies include CDR-grafting (complementarity determining region grafting) (EP 0 239 400; WO 91/09967; U.S. Pat. Nos. 5,530,101; and 5,585,089), veneering or resurfacing (EP 0 592 106; EP 0 519 596; Padlan, 199; Studnicka et al., 1994; Roguska et al., 1994), chain shuffling (U.S. Pat. No. 5,565,332) and DeImmunosationTM (Biovation, LTD).
  • CDR-grafting complementarity determining region grafting
  • EP 0 239 400 WO 91/09967
  • veneering or resurfacing EP 0 592 106;
  • CDR-grafting the mouse complementarity-determining regions (CDRs) from, for example, mAb B-B4 are grafted into human variable frameworks, which are then joined to human constant regions, to create a human B-B4 antibody (hB-B4).
  • CDRs mouse complementarity-determining regions
  • hB-B4 antibody human B-B4 antibody
  • the resurfacing technology uses a combination of molecular modeling, statistical analysis and mutagenesis to alter the non-CDR surfaces of antibody variable regions to resemble the surfaces of known antibodies of the target host.
  • Strategies and methods for the resurfacing of antibodies, and other methods for reducing immunogenicity of antibodies within a different host, are disclosed, for example, in U.S. Pat. No. 5,639,641.
  • Human antibodies can be made by a variety of methods known in the art including phage display methods. See also U.S. Pat. Nos.
  • Targeting antibodies that have undergone any non-natural modification such as chimeric human/mouse antibodies or a chimeric human/monkey antibodies, humanized antibodies or antibodies that were engineered to, for example, improve their affinity to the target cells or diminish their immunogenicity but also antibody fragments, in particular functional fragments of such targeting antibodies that have undergone any non-natural modification, diabodies; domain antibodies; linear antibodies; single-chain antibody molecules; and multispecific antibodies are referred to herein as engineered targeting antibodies.
  • Chimerized antibodies maintain the antibody binding region (ABR or Fab region) of the non-human antibody, e.g., the murine antibody they are based on, while any constant regions may be provided for by, e.g., a human antibody.
  • chimerization and/or the exchange of constant regions of an antibody will not affect the affinity of an antibody because the regions of the antibody which contribute to antigen binding are not affected by this exchange.
  • the engineered, in particular chimerized, antibody of the present invention may have a higher binding affinity (as expressed by K D values) than the respective non-human antibody it is based on.
  • the nBT062 antibody and antibodies based thereon may have higher antibody affinity than the murine B-B4.
  • immunoconjugates comprising those engineered/chimerized antibodies also display this higher antibody affinity. These immunconjugates may also display in certain embodiments other advantageous properties, such as a higher reduction of tumor load than their B-B4 containing counterparts.
  • the engineered, in particular chimerized targeting antibodies display binding affinities that are characterized by dissociation constants K D (nM) of less than 1.6, less than 1.5 or about or less than 1.4, while their murine counterparts are characterized by dissociation constants K D (nM) of about or more than 1.6.
  • Immunoconjugates comprising targeting agents such as targeting antibodies may be characterized by dissociation constants of K D (nM) of less than 2.6, less than 2.5, less than 2.4, less than 2.3, less than 2.2, less than 2.1, less than 2.0, less than or about 1.9 are preferred, while immunoconjugates comprising the murine counterpart antibodies may be characterized by dissociation constants K D (nM) of about or more than 2.6 (compare Table 3, Materials and Methods).
  • Fully human antibodies may also be used. Those antibodies can be selected by the phage display approach, where CD138 or an antigenic determinant thereof is used to selectively bind phage expressing, for example, B-B4 variable regions (see, Krebs, 2001). This approach is advantageously coupled with an affinity maturation technique to improve the affinity of the antibody. All antibodies referred to herein are isolated antibodies.
  • the targeting antibody is, in its unconjugated form, moderately or poorly internalized. Moderate internalization constitutes about 30% to about 75% internalization of antibody, poor internalization constitutes about 0.01% to up to about 30% internalization after 3 hours incubation at 37° C.
  • the targeting antibody binds to CD138, for example, antibodies B-B4, BC/B-B4, B-B2, DL-101, 1 D4, MI15, 1.BB.210, 2Q1484, 5F7, 104-9, 281-2 in particular B-B4.
  • Hybridoma cells which were generated by hybridizing SP02/0 myeloma cells with spleen cells of Balb/c mice have been deposited with the DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1, D-38124 Braunschweig on Dec. 11, 2007.
  • the identification number of these B-B4 expressing hybridoma cells is DSM ACC2874.
  • the targeting antibody does not substantially bind non-cell-surface expressed CD138.
  • the term “targeting antibody” such as “nBT062 targeting antibody,” this means that this targeting antibody has the binding specificity of the antibody nBT062.
  • a targeting antibody is said to be “based on” a specified antibody, this means that this targeting antibody has the binding specificity of this antibody, but might take any form consistent with the above description of a targeting antibody.
  • the name of a specific antigen is combined with the term “targeting antibody” such as “CD138 targeting antibody,” this means that this targeting antibody has the binding specificity for CD138.
  • a targeting antibody is said to do something “selectively” such as “selectively targeting cell-surface expressed CD138” or, to be “selective” for something, this means that there is a significant selectivity (i.e.
  • Non-immunoglobulin targeting molecules include targeting molecules derived from non-immunoglobulin proteins as well as non-peptidic targeting molecules.
  • Small non-immunoglobulin proteins which are included in this definition are designed to have specific affinities towards, in particular surface expressed CD138.
  • These small non-immunoglobulin proteins include scaffold based engineered molecules such as Affilin® molecules that have a relatively low molecular weight such as between 10 kDa and 20 kDa.
  • Appropriate scaffolds include, for example, gamma crystalline. Those molecules have, in their natural state, no specific binding activity towards the target molecules. By engineering the protein surfaces through locally defined randomization of solvent exposed amino acids, completely new binding sites are created.
  • Non-binding proteins are thereby transformed into specific binding proteins.
  • Such molecules can be specifically designed to bind a target, such as CD138, and allow for specific delivery of one or more effector molecules (see, scil Proteins GmbH at the company's website, 2004).
  • Another kind of non-immunoglobulin targeting molecules are derived from lipocalins, and include, for example ANTICALINS®, which resemble in structure somewhat immunoglobulins.
  • lipocalins are composed of a single polypeptide chain with 160 to 180 amino acid residues. The binding pocket of lipocalins can be reshaped to recognize a molecule of interest with high affinity and specificity (see, for example, Beste et al., 1999).
  • Artificial bacterial receptors such as those marketed under the trademark Affibody® (Affibody AB) are also within the scope of the present invention.
  • These artificial bacterial receptor molecules are small, simple proteins and may be composed of a three-helix bundle based on the scaffold of one of the IgG-binding domains of Protein A ( Staphylococcus aureus ). These molecules have binding properties similar to many immunoglobulins, but are substantially smaller, having a molecular weight often not exceeding 10 kDa and are also comparatively stable.
  • Suitable artificial bacterial receptor molecules are, for example, described in U.S. Pat. Nos. 5,831,012; 6,534,628 and 6,740,734.
  • effector molecule is a molecule or a derivative, or an analogue thereof that is attached to a targeting agent, in particular a targeting antibody and/or an engineered targeting antibody, and that exerts a desired effect, for example, apoptosis, or another type of cell death, or a continuous cell cycle arrest on the target cell or cells.
  • Effector molecules according to the present invention include molecules that can exert desired effects in a target cell and include, but are not limited to, toxins, drugs, in particular low molecular weight cytotoxic drugs, radionuclides, biological response modifiers, pore-forming agents, ribonucleases, proteins of apoptotic signaling cascades with apoptosis-inducing activities, cytotoxic enzymes, prodrug activating enzymes, antisense oligonucleotides, antibodies or cytokines as well as functional derivatives or analogues/fragments thereof.
  • toxins drugs, in particular low molecular weight cytotoxic drugs, radionuclides, biological response modifiers, pore-forming agents, ribonucleases, proteins of apoptotic signaling cascades with apoptosis-inducing activities, cytotoxic enzymes, prodrug activating enzymes, antisense oligonucleotides, antibodies or cytokines as well as functional derivatives or analogue
  • Toxins may include bacterial toxins, such as, but not limited to, Diphtheria toxin or Exotoxin A, plant toxins, such as but not limited to, Ricin.
  • Proteins of apoptotic signaling cascades with apoptosis-inducing activities include, but are not limited to, Granzyme B, Granzyme A, Caspase-3, Caspase-7, Caspase-8, Caspase-9, truncated Bid (tBid), Bax and Bak.
  • the effector increases internal effector delivery of the immunoconjugate, in particular when the natural form of the antibody on which the targeting antibody of the immunoconjugate is based is poorly internalizable.
  • the effector is, in its native form, non-selective.
  • the effector has high non-selective toxicity, including systemic toxicity, when in its native form.
  • the “native form” of an effector molecule of the present invention is an effector molecule before being attached to the targeting agent to form an immunoconjugate.
  • the non-selective toxicity of the effector molecule is substantially eliminated upon conjugation to the targeting agent.
  • the effector molecule causes, upon reaching the target cell, death or continuous cell cycle arrest in the target cell.
  • a drug-effector molecule according to the present invention includes, but is not limited to, a drug including, for example, small highly cytotoxic drugs that act as inhibitors of tubulin polymerization such as maytansinoids, dolastatins, auristatin and crytophycin; DNA alkylating agents like CC-1065 analogues or derivatives (U.S. Pat. Nos.
  • An effector maytansinoid includes maytansinoids of any origin, including, but not limited to synthetic maytansinol and maytansinol analogue and derivative.
  • Doxorubicin, daunomycin, methotrexate, vinblastine, neocarzinostatin, macromycin, trenimon and ⁇ -amanitin are some other effector molecules within the scope of the present invention.
  • antisense DNA molecules as effector molecules.
  • effector or effector molecule
  • Maytansine is a natural product originally derived from the Ethiopian shrub Maytenus serrata (Remillard, 1975; U.S. Pat. No. 3,896,111). This drug inhibits tubulin polymerization, resulting in mitotic block and cell death (Remillard, 1975; Bhattacharyya, 1977; Kupchan, 1978).
  • the cytotoxicity of maytansine is 200-1000-fold higher than that of anti-cancer drugs in clinical use that affect tubulin polymerization, such as Vinca alkaloids or taxol.
  • clinical trials of maytansine indicated that it lacked a therapeutic window due to its high systemic toxicity.
  • Maytansine and maytansinoids are highly cytotoxic but their clinical use in cancer therapy has been greatly limited by their severe systemic side-effects primarily attributed to their poor selectivity for tumors. Clinical trials with maytansine showed serious adverse effects on the central nervous system and gastrointestinal system.
  • Maytansinoids have also been isolated from other plants including seed tissue of Trewia nudiflora (U.S. Pat. No. 4,418,064)
  • Certain microbes also produce maytansinoids, such as maytansinol and C-3 maytansinol esters (U.S. Pat. No. 4,151,042).
  • the present invention is directed to maytansinoids of any origin, including synthetic maytansinol and maytansinol analogues which are disclosed, for example, in U.S. Pat. Nos. 4,137,230; 4,248,870; 4,256,746; 4,260,608; 4,265,814; 4,294,757; 4,307,016; 4,308,268; 4,308,269; 4,309,428; 4,313,946; 4,315,929; 4,317,821; 4,322,348; 4,331,598; 4,361,650; 4,362,663; 4,364,866; 4,371,533; 4,424,219 and 4,151,042.
  • the maytansinoid is a thiol-containing maytansinoid and is more preferably produced according to the processes disclosed in U.S. Pat. No. 6,333,410 to Chari et al or in Chari et al. (Chari, 1992).
  • DM-1 (N 2 -deacetyl-N 2 -(3-mercapto-1-oxopropyl)-maytansine) is a preferred effector molecule in the context of the present invention.
  • DM1 is 3- to 10-fold more cytotoxic than maytansine, and has been converted into a pro-drug by linking it via disulfide bond(s) to a monoclonal antibody directed towards a tumor-associated antigen.
  • Certain of these conjugates (sometimes called “tumor activated prodrugs” (TAPs)) are not cytotoxic in the blood compartment, since they are activated upon associating with a target cells and internalized, thereby releasing the drug (Blättler, 2001).
  • Suitable maytansinoids comprise a side chain that contains a sterically hindered thiol bond such as, but not limited to, maytansinoids N 2′ -deacetyl-N 2′ -(4-mercapto-1-oxopentyl)-maytansine, also referred to as “DM3,” and N 2′ -deacetyl-N 2′ -(4-methyl-4-mercapto-1-oxopentyl)-maytansine, also referred to as “DM4.”
  • the synthesis of DM4 is shown in FIGS. 3 and 4 and is described elsewhere herein.
  • DM4 differs from DM1 and DM3 in that it bears methyl groups at its ⁇ C.
  • Patent Publication 2006/0233814 such a hindrance induces alkylation (e.g., methylation) of the free drug, once the drug is released at its target.
  • alkylation e.g., methylation
  • the alkylation may increase the stability of the drug allowing for the so-called bystander effect.
  • other effector molecules comprising substitutents such as alkyl groups at positions that result in a sterical hindrance when the effector is attached to a targeting agent via a linker are part of the present invention.
  • this hindrance induces a chemical modification such as alkylation of the free drug to increase its overall stability, which allows the drug to not only induce cell death or continuous cell cycle arrest in CD138 expressing tumor cells but, optionally, also to affect auxiliary cells that, e.g., support or protect the tumor from drugs, in particular cells of the tumor stroma and the tumor vasculature and which generally do not express CD138 to diminish or lose their supporting or protecting function.
  • a chemical modification such as alkylation of the free drug to increase its overall stability, which allows the drug to not only induce cell death or continuous cell cycle arrest in CD138 expressing tumor cells but, optionally, also to affect auxiliary cells that, e.g., support or protect the tumor from drugs, in particular cells of the tumor stroma and the tumor vasculature and which generally do not express CD138 to diminish or lose their supporting or protecting function.
  • DNA alkylating agents are also particularly preferred as effector molecules and include, but are not limited to, CC-1065 analogues or derivatives.
  • CC-1065 is a potent antitumor-antibiotic isolated from cultures of Streptomyces zelensis and has been shown to be exceptionally cytotoxic in vitro (U.S. Pat. No. 4,169,888).
  • CC-1065 analogues or derivatives described in U.S. Pat. Nos. 5,475,092, 5,585,499 and 5,739,350.
  • modified CC-1065 analogues or derivatives as described in U.S. Pat. No.
  • CC-1065 analogues or derivatives as described, for example, in U.S. Pat. No. 6,756,397 are also within the scope of the present invention.
  • CC-1065 analogues or derivatives may, for example, be synthesized as described in U.S. Pat. No. 6,534,660.
  • Taxanes are mitotic spindle poisons that inhibit the depolymerization of tubulin, resulting in an increase in the rate of microtubule assembly and cell death.
  • Taxanes that are within the scope of the present invention are, for example, disclosed in U.S. Pat. Nos. 6,436,931; 6,340,701; 6,706,708 and United States Patent Publications 20040087649; 20040024049 and 20030004210.
  • Other taxanes are disclosed, for example, in U.S. Pat. No. 6,002,023, U.S. Pat. No. 5,998,656, U.S. Pat. No.
  • Calicheamicin effector molecules include gamma 1I, N-acetyl calicheamicin and other derivatives of calicheamicin.
  • Calicheamicin binds in a sequence-specific manner to the minor groove of DNA, undergoes rearrangement and exposes free radicals, leading to breakage of double-stranded DNA, resulting in cell apoptosis and death.
  • a calicheamicin effector molecule that can be used in the context of the present invention is described in U.S. Pat. No. 5,053,394.
  • An immunoconjugate according to the present invention comprises at least one targeting agent, in particular targeting antibody, such as an engineered targeting antibody, and one effector molecule.
  • the immunoconjugate might comprise further molecules for example for stabilization.
  • the term “conjugate” is generally used to define the operative association of the targeting agent with one or more effector molecules and is not intended to refer solely to any type of operative association, and is particularly not limited to chemical “conjugation”. So long as the targeting agent is able to bind to the target site and the attached effector functions sufficiently as intended, particularly when delivered to the target site, any mode of attachment will be suitable.
  • the conjugation methods according to the present invention include, but are not limited to, direct attachment of the effector molecule to the targeting antibody, with or without prior modification of the effector molecule and/or the targeting antibody or attachment via linkers.
  • Linkers can be categorized functionally into, for example, acid labile, photolabile linkers, enzyme cleavable linkers, such as linkers that can be cleaved by peptidases. Cleavable linkers are, in many embodiments of the invention preferred. Such cleavable linkers can be cleaved under conditions present in the cellular environment, in particular, an intracellular environment and that have no detrimental effect on the drug released upon cleavage.
  • Preferred heterobifunctional disulfide linkers include, but are not limited to, N-succinimidyl 3-(2-pyridyldithio)propionate (SPDP) (see, e.g., Carlsson et al. (1978)), N-succinimidyl 4-(2-pyridyldithio)butanoate (SPDB) (see, e.g., U.S. Pat. No.
  • N-succinimidyl 4-(2-pyridyldithio)pentanoate SPP
  • SPP N-succinimidyl 4-(N-maleimidomethyl)cyclohexane-1-carboxylate
  • SMCC N-maleimidomethylcyclohexane-1-carboxylate
  • SMNP N-succinimidyl 4-methyl-4-[2-(5-nitro-pyridyl)-dithio]pentanoate
  • the most preferred linker molecules for use in the inventive composition are SPP, SMCC, and SPDB.
  • linkers may include “non-cleavable” bonds, such as, but not limited to Sulfosuccinimidyl maleimidomethyl cyclohexane carboxylate (SMCC), which is a heterobifunctional linker capable of linking compounds with SH-containing compounds.
  • Sulfosuccinimidyl maleimidomethyl cyclohexane carboxylate SMCC
  • bifunctional and heterobifunctional linker molecules such as carbohydrate-directed heterobifunctional linker molecules, such as S-(2-thiopyridyl)-L-cysteine hydrazide (TPCH), are also within the scope of the present invention (Vogel, 2004).
  • the effector molecule such as a maytansinoid
  • a two reaction step process including as a first step modification of the targeting antibody with a cross-linking reagent such as N-succinimidyl pyridyldithiopropionate (SPDP) to introduce dithiopyridyl groups into the targeting antibody.
  • SPDP N-succinimidyl pyridyldithiopropionate
  • a reactive maytansinoid having a thiol group such as DM1
  • DM1 a reactive maytansinoid having a thiol group
  • CC-1065 analogues or derivatives may be conjugated to the targeting agent via for example PEG linking groups as described in U.S. Pat. No. 6,716,821.
  • Calicheamicins may be conjugated to the targeting antibodies via linkers (U.S. Pat. No. 5,877,296 and U.S. Pat. No. 5,773,001) or according to the conjugation methods disclosed in U.S. Pat. No. 5,712,374 and U.S. Pat. No. 5,714,586.
  • Another preferred method for preparing calicheamicin conjugates is disclosed in Unites States Patent Publication 20040082764.
  • the immunoconjugates of the present invention may take the form of recombinant fusion proteins.
  • sequence identity refers to a measure of the identity of nucleotide sequences or amino acid sequences. In general, the sequences are aligned so that the highest order match is obtained. “Identity”, per se, has recognized meaning in the art and can be calculated using published techniques. (See, e.g.: Computational Molecular Biology, Lesk, A. M., ed., Oxford University Press, New York, 1988; Biocomputing: Informatics and Genome Projects, Smith, D. W., ed., Academic Press, New York, 1993; Computer Analysis of Sequence Data, Part I, Griffin, A. M., and Griffin, H.
  • nucleic acid molecule is at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance, the nBT062 nucleic acid sequence, or a part thereof, can be determined conventionally using known computer programs such as DNAsis software (Hitachi Software, San Bruno, Calif.) for initial sequence alignment followed by ESEE version 3.0 DNA/protein sequence software (cabot@trog.mbb.sfu.ca) for multiple sequence alignments.
  • DNAsis software Haitachi Software, San Bruno, Calif.
  • ESEE version 3.0 DNA/protein sequence software cabot@trog.mbb.sfu.ca
  • amino acid sequence is at least 50%, 60%, 70%, 75%, 80%, 85%, 90%, 95%, 96%, 97%, 98% or 99% identical to, for instance SEQ ID NO:1 or SEQ ID NO:2, or a part thereof, can be determined conventionally using known computer programs such the BESTFIT program (Wisconsin Sequence Analysis Package, Version 8 for Unix, Genetics Computer Group, University Research Park, 575 Science Drive, Madison, Wis. 53711).
  • BESTFIT uses the local homology algorithm of Smith and Waterman, Advances in Applied Mathematics 2:482-489 (1981), to find the best segment of homology between two sequences.
  • the parameters are set such that the percentage of identity is calculated over the full length of the reference nucleic acid or amino acid sequence and that gaps in homology of up to 5% of the total number of nucleotides in the reference sequence are allowed.
  • sequence identity relates to the sum of all the residues specified.
  • the basic antibody molecule is a bifunctional structure wherein the variable regions bind antigen while the remaining constant regions may elicit antigen independent responses.
  • the major classes of antibodies, IgA, IgD, IgE, IgG and IgM, are determined by the constant regions. These classes may be further divided into subclasses (isotypes). For example, the IgG class has four isotypes, namely, IgG1, IgG2, IgG3, and IgG4 which are determined by the constant regions. Of the various human antibody classes, only human IgG1, IgG2, IgG3 and IgM are known to effectively activate the complement system. While the constant regions do not form the antigen binding sites, the arrangement of the constant regions and hinge region may confer segmental flexibility on the molecule which allows it to bind with the antigen.
  • Different IgG isotypes can bind to Fc receptors on cells such as monocytes, B cells and NK cells, thereby activating the cells to release cytokines. Different isotypes may also activate complement, resulting in local or systemic inflammation. In particular, the different IgG isotypes may bind Fc ⁇ R to different degrees.
  • Fc ⁇ Rs are a group of surface glycoproteins belonging to the Ig superfamily and expressed mostly on leucocytes. The Fc ⁇ R glycoproteins are divided into three classes designated Fc ⁇ RI (CD64), Fc ⁇ RII (CD32) and Fc ⁇ RIII (CD16).
  • IgG4 While IgG1, IgG2 and IgG3 bind strongly to a variety of these classes of Fc ⁇ R glycoproteins, IgG4 display much weaker binding.
  • IgG4 is an intermediate binder of Fc ⁇ RI, which results in relatively low or even no ADCC (antibody dependent cellular cytotoxicity), and does not bind to Fc ⁇ RIIIA or Fc ⁇ RIIA.
  • IgG4 is also a weak binder of Fc ⁇ RIIB, which is an inhibitory receptor.
  • IgG4 mediates only weak or no complement fixation and weak or no complement dependent cytotoxicity (CDC).
  • IgG4 may be specifically employed to prevent Fc-mediated targeting of hepatic FcR as it displays no interaction with FcR ⁇ II on LSECs (liver sinusoidal endothelial cells), no or weak interaction with FcR ⁇ I-III on Kupffer cells (macrophages) and no interaction with FcR ⁇ III on hepatic NK cells.
  • Certain mutations that further reduce any CDC are also part of the present invention. For example IgG4 residues at positions 327, 330 and 331 were shown to reduce ADCC (antibody dependent cellular cytotoxicity) and CDC (Amour, 1999; Shields, 2001).
  • One of more mutations that stabilize the antibody are also part of the present invention (also referred to herein as “stabilizing mutations”).
  • Those mutations include in particular, leucine-to-glutamic acid mutations in the CH2 region of IgG4 and serine-to-proline exchanges in the IgG4 hinge core. These mutations decrease, in certain embodiments of the invention, the amount of half-molecules to less than 10%, less than 5% and preferably less than 2% or 1%.
  • the in vivo half life of so stabilized antibodies might be increased several days, including 1, 2, 3, 4 or more than 5 days (Schuurman, 1999).
  • Targeting agents including targeting antibodies, in particular engineered targeting antibodies, disclosed herein may also be described or specified in terms of their binding affinity to antigen, in particular to CD138.
  • Preferred binding affinities of targeting agents such as targeting antibodies, in particular engineerend targeting antibodies, are characterized by dissociation constants K D (nM) of less than 1.6, less than 1.5 or about or less than 1.4.
  • dissociation constants K D (nM) are preferred for immunoconjugates comprising said targeting agents such as targeting antibodies.
  • An antigen binding region (ABR) will vary based on the type of targeting antibody or engineered targeting antibody employed.
  • the antigen binding region In a naturally occurring antibody and in most chimeric and humanized antibodies, the antigen binding region is made up of a light chain and the first two domains of a heavy chain. However, in a heavy chain antibody devoid of light chains, the antigen binding region will be made up of, e.g., the first two domains of the heavy chain only, while in single chain antibodies (ScFv), which combine in a single polypeptide chain the light and heavy chain variable domains of an antibody molecule, the ABR is provided by only one polypeptide molecule.
  • FAB fragments are usually obtained by papain digestion and have one light chain and part of a heavy chain and thus comprise an ABR with only one antigen combining site.
  • diabodies are small antibody fragments with two antigen-binding regions.
  • an antigen binding region of an targeting antibody or engineered targeting antibody is any region that primarily determines the binding specificity of the targeting antibody or engineered targeting antibody.
  • an ABR or another targeting antibody region is said to be “of a certain antibody”, e.g., a human or non-human antibody, this means in the context of the present invention that the ABR is either identical to a corresponding naturally occurring ABR or is based thereon.
  • An ABR is based on a naturally occurring ABR if it has the binding specificity of the naturally occurring ABR.
  • such an ABR may comprise, e.g., point mutations, additions, deletions or posttranslational modification such as glycosylation.
  • Such an ABR may in particular have more than 70%, more than 80%, more than 90%, preferably more than 95%, more than 98% or more than 99% sequence identity with the sequence of the naturally occurring ABR.
  • Homogenous targeting of a targeting agent such as a targeting antibody, but in particular an immunoconjugate comprising the same, in the context of the present invention is a measure of the variance associated with obtaining the desired result of said targeting with the targeting agent.
  • the desired result is obtained by simple binding to the target. This is, for example, the case in embodiments in which a certain targeting agent provides a shield against subsequent binding.
  • the homogeneity of a targeting agent can be readily assessed, e.g., via the efficacy of an immunoconjugate comprising said targeting agent.
  • the efficacy of said immunoconjugate against a tumor antigen such as CD138 that comprises an effector aimed at destroying tumor cells and/or arresting the growth of a tumor can be determined by the degree of growth suppression of a tumor comprising cells expressing the CD138 antigen.
  • a tumor antigen such as CD138 that comprises an effector aimed at destroying tumor cells and/or arresting the growth of a tumor
  • Such an immunoconjugate may display a high variance in its efficacy. It may, for example, arrest tumor growth sometimes with high efficacy, but other times with an efficacy that hardly exceeds the efficacy of the control.
  • a low variance in the efficacy of an immunoconjugate shows that the immunoconjugate and/or targeting agent, respectively, provide the desired result consistently.
  • One way of quantifying the homogeneity of targeting is to calculate the targeting variation.
  • the targeting variation can be calculated by first determining the time for a tumor to reach a predetermined volume, e.g. 300 mm 3 .
  • a predetermined volume e.g. 300 mm 3 .
  • the predetermined volume is chosen so that any tumor growth before and after reaching said predetermined volume is steadily increasing at about the same rate.
  • T m the mean of these times (T m ) in the group of subjects (e.g., SCID mice or another suitable model displaying homogenous tumor growth) is calculated.
  • the targeting variation of the engineered targeting antibody of the present invention is less than 150%, less than 140%, less than 130%, less than 120%, less than 110%, less than 100%, less than 90%, less than 80%, less than 70%, less than 60%, or less than 50%, and in certain embodiments even less than 45%.
  • the targeting variation is between about 10% and about 150%, preferably between about 10% and about 100%, about 10% and about 80%, about 10% and about 70%, about 10% and about 60%, about 10% and about 50%.
  • the homogenity of targeting (also referred to herein as the homogenity of binding to a particular antigen) can be also quantified by other means such as determining the tumor growth delay. Also, as the person skilled in the art will readily understand tumor volume of a certain size is only one parameter on which basis targeting variation may be determined. Depending on the desired result, other parameters include time (for, e.g., measuring tumor growth delay) or % of binding may be employed. The person skilled in the art can readily determine such other parameters.
  • nBT062 (see also FIG. 1 ) is a murine human chimeric IgG4 mAb a chimerized version of B-B4. This chimerized version of B-B4 was created to reduce the HAMA (Human Anti-Mouse Antibody) response, while maintaining the functionality of the antibody binding region of the B-B4 for CD138. Surprisingly it was found that this chimeric antibody displays improved binding affinities relative to B-B4. Also surprisingly, the chimeric antibody has been associated with homogenous targeting, which reduces the variance in results obtained when using the antibody or immunoconjugate comprising the same. The protocol for producing nBT062 is specified below.
  • nBT062 Chinese hamster ovary cells expressing nBT062 have been deposited with the DSMZ-Deutsche Sammlung von Mikroorganismen und Zellkulturen GmbH, Mascheroder Weg 1, D-38124 Braunschweig on Dec. 11, 2007. The identification number is DSM ACC2875.
  • a CD138 specific chimeric antibody based on B-B4 is generically referred to herein as c-B-B4.
  • amino acid sequence for both, the heavy and the light chains has been predicted from the translation of the nucleotide sequence for nBT062.
  • amino acid sequences predicted for the heavy chain and light chain are presented in Table 1. Predicted variable regions are bolded, predicted CDRs are underlined.
  • nBT062 heavy chain predicted sequence (SEQ ID NO:1): 1 QVQLQQSGSE LMMPGASVKI SCKATGYTFS NYWIE WVKQR PGHGLEWIGE 51 ILPGTGRTIY NEKFKGKA TF TADISSNTVQ MQLSSLTSED SAVYYCAR RD 101 YYGNFYYAMD Y WGQGTSVTV SS ASTKGPSV FPLAPCSRST SESTAALGCL 151 VKDYFPEPVT VSWNSGALTS GVHTFPAVLQ SSGLYSLSSV VTVPSSSLGT 201 KTYTCNVDHK PSNTKVDKRV ESKYGPPCPS CPAPEFLGGP SVFLFPPKPK 251 DTLMISRTPE VTCVVVDVSQ EDPEVQFNWY VDGVEVHNAK TKPREEQFNS 301 TYRVVSVLTV LHQD
  • nBT062 light chain predicted sequence (SEQ ID NO:2): 1 DIQMTQSTSS LSASLGDRVT ISCS ASQGIN NYLN WYQQKP DGTVELLIYY 51 TSTLQS GVPS RFSGSGSGTD YSLTISNLEP EDIGTYYC QQ YSKLPRT FGG 101 GTKLEIK RTV AAPSVFIFPP SDEQLKSGTA SVVCLLNNFY PREAKVQWKV 151 DNALQSGNSQ ESVTEQDSKD STYSLSSTLT LSKADYEKHK VYACEVTHQG 201 LSSPVTKSFN RGEC
  • BT062 is an immunoconjugate comprising the CD138 targeting chimeric antibody nBT062 that is attached via a linker, here SPDB, to the cytostatic maytansinoid derivative DM4.
  • a chemical representation of BT062 is provided in FIGS. 1 and 2 .
  • Immunoconjugates comprising nBT062 and a maytansinoid effector molecule are often characterized in terms of their linker and maytansinoid effector, e.g., nBT062-SMCC-DM1, is an immunoconjugate comprising nBT062, SMCC (a “noncleavable” linker containing a thioester bond) and DM1 as an effector.
  • an immunoconjugate containing nBT062 and an effector molecule may also be described as nBT062-linker-effector or just as nBT062-effector (nBT062N, wherein N is any effector described herein.
  • UI unhindered immunoconjugate
  • UICL unhindered immunoconjugate
  • HICL cleavable linker
  • BT062 and nBT062-SPP-DM1 examples of a pair of HICL/UICL.
  • An unhindered counterpart of such a immunoconjugate comprising a non-cleavable linker refers to the equivalent immunoconjugate comprising an engineered targeting antibody in which the effector molecule is not sterically hindered and comprises a noncleavable linker.
  • nBT062-SMCC-DM1 would constitute an example of such an unhindered counterpart comprising an non-cleavable linker.
  • the activity of the highest performing immunoconjugate say, BT062, which causes a tumor growth delay (TGD) of 32 days
  • Table 3 provides suitable examples from the results depicted in FIG. 11B :
  • TGD Tumor growth delay
  • BT062 provides a growth of a tumor inhibiting activity that exceeds that of its unhindered counterpart (nBT062-SPP-DM1) by 60%, and a growth of a tumor inhibiting activity that exceeds that of its unhindered counterpart immunoconjugate comprising a non-cleavable linker (nBT062-SMCC-DM1) by 44%.
  • the targeting agents in particular targeting antibodies, and/or immunoconjugates disclosed herein can be administered by any route, including intravenously, parenterally, orally, intramuscularly, intrathecally or as an aerosol.
  • the mode of delivery will depend on the desired effect. A skilled artisan will readily know the best route of administration for a particular treatment in accordance with the present invention. The appropriate dosage will depend on the route of administration and the treatment indicated, and can readily be determined by a skilled artisan in view of current treatment protocols.
  • compositions containing an unconjugated targeting agent and the immunoconjugate of the present invention as active ingredients can be prepared according to conventional pharmaceutical compounding techniques. See, for example, Remington's Pharmaceutical Sciences, 17th Ed. (1985, Mack Publishing Co., Easton, Pa.). Typically, effective amounts of active ingredients will be admixed with a pharmaceutically acceptable carrier.
  • the carrier may take a wide variety of forms depending on the form of preparation desired for administration, for example, intravenous, oral, parenteral, intrathecal, transdermal, or by aerosol.
  • the targeting agent and/or immunoconjugate can be formulated into solid or liquid preparations such as capsules, pills, tablets, lozenges, melts, powders, suspensions or emulsions.
  • any of the usual pharmaceutical media may be employed, such as, for example, water, glycols, oils, alcohols, flavoring agents, preservatives, coloring agents, suspending agents, and the like in the case of oral liquid preparations (such as, for example, suspensions, elixirs and solutions); or carriers such as starches, sugars, diluents, granulating agents, lubricants, binders, disintegrating agents and the like in the case of oral solid preparations (such as, for example, powders, capsules and tablets).
  • tablets and capsules represent the most advantageous oral dosage unit form, in which case solid pharmaceutical carriers are obviously employed. If desired, tablets may be sugar-coated or enteric-coated by standard techniques.
  • the active agent must be stable to passage through the gastrointestinal tract. If necessary, suitable agents for stable passage can be used, and may include phospholipids or lecithin derivatives described in the literature, as well as liposomes, microparticles (including microspheres and macrospheres).
  • the targeting agent and/or the immunoconjugate may be dissolved in a pharmaceutical carrier and administered as either a solution or a suspension.
  • suitable carriers are water, saline, phosphate buffer solution (PBS), dextrose solutions, fructose solutions, ethanol, or oils of animal, vegetative or synthetic origin.
  • PBS phosphate buffer solution
  • the carrier may also contain other ingredients, for example, preservatives, suspending agents, solubilizing agents, buffers and the like.
  • the unconjugated targeting agent and/or immunoconjugate When the unconjugated targeting agent and/or immunoconjugate are being administered intracerebroventricularly or intrathecally, they may also be dissolved in cerebrospinal fluid.
  • Dosages administered to a subject may be specified as amount, per surface area of the subject (which include humans as well as non-human animals).
  • the dose may be administered to such a subject in amounts, preferably, but not exclusively from about 5 mg/m 2 to about 300 mg/m 2 , including about 20 mg/m 2 , about 50 mg/m 2 , about 100 mg/m 2 , about 150 mg/m 2 , about 200 mg/m 2 and about 250 mg/m 2 .
  • the targeting agents/immunoconjugates are suitably administered at one time or over a series of treatments. In a multiple dose regime these amounts may be administered once a day, once a week, once every two weeks, once every three weeks, once every four weeks, one every five weeks or once every six weeks.
  • Loading doses with a single high dose or, alternatively, lower doses that are administered shortly after one another followed by dosages timed at longer intervals constitute a preferred embodiment of the present invention.
  • the timing of the dosages are adjusted for a subject so that enough time has passed prior to a second and/or any subsequent treatment so that the previous dose has been metabolized substantially, but the amount of immunoconjugate present in the subject's system still inhibits, delays and/or prevents the growth of a tumor.
  • An exemplary “repeated single dose” regime comprises administering an initial dose of immunoconjugate of about 200 mg/m 2 once every three weeks.
  • a high initial dose may be followed by a biweekly maintenance dose of about 150 ⁇ g/m 2 .
  • dosage regimens may be useful.
  • the progress of this therapy is easily monitored by known techniques and assays. Dosage may vary depending on whether they are administered for preventive or therapeutic purposes, the course of any previous therapy, the patient's clinical history and response to the targeting agent/immunoconjugate, and the discretion of the attending physician.
  • MM is treated as follows, with the use of nBT062 and BT062 as an example. This example is not intended to limit the present invention in any manner, and a skilled artisan could readily determine other immunoconjugate and nBT062 based systems that are within the scope of the present invention and other treatment regimes which could be utilized for the treatment of diseases such as MM.
  • BT062 Due to the selective expression of CD138 on patient MM cells on via the blood stream accessible cells, the specificity of nBT062 and the stability of BT062 in the bloodstream, BT062 remove the systemic toxicity of DM4 and provides an opportunity to target the delivery of the DM4-effector molecule(s).
  • Administration of dosages of nBT062 is beneficial to shield low expressing CD138 positive, non-tumor cells against BT062 binding of those cells and preferably destruction, while the immunoconjugates provide a means for the effective administration of the effector molecules to cell sites where the effector molecules can be released from the immunoconjugates. This targeted delivery and release provides a significant advance in the treatment of multiple myeloma, for which current chemotherapy methods sometimes provide incomplete remission.
  • Murine antibody B-B4 as previously characterized (Wijdenes et al., Br J. Haematol., 94 (1996), 318) was used in these experiments.
  • Exponentially growing COS cells cultured in DMEM supplemented with 10% FCS, 580 ⁇ g/ml L-glutamine, 50 Units/ml penicillin and 50 ⁇ g/ml streptomycin were harvested by trypsinisation and centrifugation and washed in PBS. Cells were resuspended in PBS to a final concentration of 1 ⁇ 10 7 cells/ml. 700 ⁇ l of COS cell suspension was transferred to a Gene Pulser cuvette and mixed with heavy and kappa light chain expression vector DNA (10 ⁇ g each or 13 ⁇ g of Supervector). Cells were electroporated at 1900 V, 25 ⁇ F using a Bio-Rad Gene Pulser.
  • Transformed cells were cultured in DMEM supplemented with 10% gamma-globulin free FBS, 580 ⁇ g/ml L-glutamine, 50 Units/ml penicillin and 50 ⁇ g/ml streptomycin for 72 h before antibody-containing cell culture supernatants were harvested.
  • the cB-B4 antibody was purified from supernatants of transformed COS 7 cells using the Protein A ImmunoPure Plus kit (Pierce, Rockford, Ill.), according to the manufacturer's recommendation.
  • Hybridoma B-B4 cells were grown and processed using the Qiagen Midi kit (Hilden, Germany) to isolate RNA following the manufacturer's protocol. About 5 ⁇ g of B-B4 RNA was subjected to reverse transcription to produce B-B4 cDNA using the Amersham Biosciences (Piscataway, N.J.) 1st strand synthesis kit following the manufacturer's protocol.
  • Immunoglobulin heavy chain (IgH) cDNA was amplified by PCR using the IgH primer MHV7 (5′-ATGGGCATCAAGATGGAGTCACAGACCCAGG-3′) [SEQ ID NO:3] and the IgG1 constant region primer MHCG1 (5′-CAGTGGATAGACAGATGGGGG-3′) [SEQ ID NO:4].
  • immunoglobulin light chain (IgL) was amplified using the three different Ig ⁇ primers MKV2 (5′-ATGGAGACAGACACACTCCTGCTATGGGTG-3′) [SEQ ID NO:5], MKV4 (5′-ATGAGGGCCCCTGCTCAGTTTTTTGGCTTCTTG-3′) [SEQ ID NO:6] and MKV9 (5′-ATGGTATCCACACCTCAGTTCCTTG-3′) [SEQ ID NO:7], each in combination with primer MKC (5′-ACTGGATGGTGGGAAGATGG-3′) [SEQ ID NO:8]. All amplification products were directly ligated with the pCR2.1-TOPO vector using the TOPO-TA cloning kit (Invitrogen, Carlsbad, Calif.) according to the manufacturer's instruction.
  • E. coli TOP10 bacteria (Invitrogen) transformed with the ligated pCR2.1 vector constructs were selected on LB-ampicillin-Xgal agar plates. Small scale cultures were inoculated with single white colonies, grown overnight and plasmids were isolated using the QIAprep Spin Miniprep kit according to the manufacturer's instruction.
  • Plasmids were sequenced using the BigDye Termination v3.0 Cycle Sequencing Ready Reaction Kit (ABI, Foster City, Calif.). Each selected plasmid was sequenced in both directions using the 1210 and 1233 primers cycled on a GeneAmp9600 PCR machine. The electrophoretic sequence analysis was done on an ABI capillary sequencer.
  • the PCR products using MKC with MKV4 and MKV9 primers were similar to each other and differed only at the wobble positions within the leader sequence primer.
  • 1st strand synthesis was performed in three independent reactions and PCR products were cloned and sequenced from each 1st strand product. Five clones were sequenced from each 1st strand.
  • the construction of the chimeric expression vectors entails adding a suitable leader sequence to VH and V ⁇ , preceded by a BamHI restriction site and a Kozak sequence.
  • the Kozak consensus sequence is crucial for the efficient translation of a variable region sequence. It defines the correct AUG codon from which a ribosome can commence translation, and the single most critical base is the adenine (or less preferably, a guanine) at position ⁇ 3, upstream of the AUG start.
  • the leader sequence is selected as the most similar sequence in the Kabat database (Kabat et al., NIH National Technical Information Service, 1991).
  • chimeric expression vectors entails introducing a 5′ fragment of the human gamma1 constant region, up to a natural ApaI restriction site, contiguous with the 3′ end of the J region of B-B4 and, for the light chain, adding a splice donor site and HindIII site.
  • the splice donor sequence is important for the correct in-frame attachment of the variable region to its appropriate constant region, thus splicing out the V:C intron.
  • the kappa intron+CK are encoded in the expression construct downstream of the B-B4 V ⁇ sequence.
  • the gamma-4 CH is encoded in the expression construct downstream of the B-B4 VH sequence.
  • the B-B4 VH and V ⁇ genes were first carefully analyzed to identify any unwanted splice donor sites, splice acceptor sites, Kozak sequences and for the presence of any extra sub-cloning restriction sites which would later interfere with the subcloning and/or expression of functional whole antibody.
  • An unwanted HindIII site was found in the V ⁇ sequence which necessarily was removed by site-directed mutagenesis via PCR without changing the amino acid sequence.
  • the non-ambiguous B-B4 V ⁇ leader sequence independent of the PCR primer sequence, was aligned with murine leader sequences in the Kabat database.
  • the nearest match for the B-B4 VH leader was VK-10 ARS-A (Sanz et al., PNAS, 84 (1987), 1085). This leader sequence is predicted to be cut correctly by the SignalP algorithm (Nielsen et al., Protein Eng, 10 (1997); 1).
  • Primers CBB4Kfor (see above) and g2258 (5′-CGCG GGATCC ACTCACGTTTGATTTCCAGCTTGGTGCCTCC-3′ [SEQ ID NO:12]; Restriction site is underlined) were designed to generate a PCR product containing this complete leader, the B-B4 V ⁇ region, and HindIII and BamHI terminal restriction sites, for cloning into the pKN100 expression vector.
  • the forward primer, CBB4K introduces a HindIII restriction site, a Kozak translation initiation site and the VK-10 ARS-A leader sequence.
  • the reverse primer g2258 introduces a splice donor site and a BamHI restriction site. The resulting fragment was cloned into the HindIII/BamHI restriction sites of pKN100.
  • the non-ambiguous B-B4 VH leader sequence independent of the PCR primer sequence, was aligned with murine leader sequences in the Kabat database.
  • the nearest match for the B-B4 VK leader was VH17-1A (Sun et al., PNAS, 84 (1987), 214). This leader sequence is predicted to be cut correctly by the SignalP algorithm.
  • Primers cBB4Hfor (see above) and g22949 (5′-CGAT GGGCCC TTGGTGGAGGCTGAGGAGACGGTGACTGAGGTTCC-3′ [SEQ ID NO:13]; Restriction site is underlined) were designed to generate a PCR product containing VH17-1A leader, the B-B4 VH region, and terminal HindIII and ApaI restriction sites, for cloning into the pG4D200 expression vector.
  • the forward primer cBBHFor introduces a HindIII restriction site, a Kozak translation initiation site and the VH17-1A leader sequence.
  • the reverse primer g22949 introduces the 5′ end of the gamma4 C region and a natural ApaI restriction site. The resulting fragment was cloned into the HindIII/ApaI restriction sites of pG4D200, resulting in vector pG4D200cBB4.
  • COS 7 cells One vial of COS 7 cells was thawed and grown in DMEM supplemented with 10% Fetal clone I serum with antibiotics. One week later, cells (0.7 ml at 10 7 cells/ml) were electroporated with pG4D200cBB4 plus pKN100cBB4 (10 ⁇ g DNA each) or no DNA. The cells were plated in 8 ml growth medium for 4 days. Electroporation was repeated seven times.
  • a sandwich ELISA was used to measure antibody concentrations in COS 7 supernatants. Transiently transformed COS 7 cells secreted about 6956 ng/ml antibody (data not shown).
  • the Diaclone sCD138 kit has been used, a solid phase sandwich ELISA.
  • a monoclonal antibody specific for sCD138 has been coated onto the wells of the microtiter strips provided.
  • bio-B-B4 antibody is simultaneously incubated together with a dilution series of unlabeled test antibody (B-B4 or cB-B4).
  • Chimeric B-B4 was purified from COS 7 cell supernatants using the Protein A ImmunoPure Plus kit (Pierce), according to the manufacturer's recommendation (data not shown).
  • Soluble CD138 antigen from U-266 cell culture supernatant was purified by FPLC using a 1 mL “HiTrap NHS-activated HP” column coupled with B-B4. Cell culture supernatant was loaded in PBS-Buffer pH 7.4 onto the column and later on CD138 antigen was eluted with 50 mM tri-ethylamine pH 11 in 2 mL fractions. Eluted CD138 was immediately neutralised with 375 ⁇ L 1 M Tris-HCl, pH 3 to prevent structural and/or functional damages.
  • Sulfo-NHS-LC (Pierce) was used to label CD138.
  • NHS-activated biotins react efficiently with primary amino groups like lysine residues in pH 7-9 buffers to form stable amide bonds.
  • Biotinylation of CD138 50 ⁇ l of CD138 were desalted using protein desalting spin columns (Pierce).
  • the biotinylation reagent (EZ-Link Sulfo NHS-LC-Biotin, Pierce) was dissolved in ice-cooled deionised H 2 O to a final concentration of 0.5 mg/mL.
  • Biotinylation reagent and capture reagent solution were mixed having a 12 times molar excess of biotinylation reagent compared to capture reagent (50 pmol CD138 to 600 pmol biotinylation reagent) and incubated 1 h at room temperature while shaking the vial gently.
  • the unbound biotinylation reagent was removed using protein desalting columns.
  • the sensorchip (SENSOR CHIP SA, BIACORE AB) used in the BIACORE assay is designed to bind biotinylated molecules for interaction analysis in BIACORE systems.
  • the surface consists of a carboxymethylated dextran matrix pre-immobilized with streptavidin and ready for high-affinity capture of biotinylated ligands. Immobilization of bCD138 was performed on SENSOR CHIP SA using a flow rate of 10 ⁇ L/min by manual injection. The chip surface was conditioned with three consecutive 1-minute injections of 1 M NaCl in 50 mM NaOH. Then biotinylated CD138 was injected for 1 minute.
  • BIACORE C uses pre-defined masks, so called “Wizards” for different experiments where only certain settings can be changed.
  • the wizard for “non-specific binding” could be used to measure affinity rate constants and was therefore used for K D -determination.
  • Regeneration 1 which is equivalent to the real regeneration was performed with 10 mM Glycine-HCl pH 2.5. After this step, the ligand CD138 was in its binding competent state again.
  • HBS-EP was used as running and dilution buffer.
  • association and dissociation was analysed at different concentrations (100, 50, 25 12.5, 6.25 and 3.13 nM).
  • the dissociation equilibrium constants were determined by calculating the rate constants ka and kd.
  • the K D -values of the analytes were calculated by the quotient of kd and ka with the BIAevaluation software. The results are shown in Table 4.
  • the thiol-containing maytansinoid DM1 was synthesized from the microbial fermentation product ansamitocin P-3, as previously described by Chari (Chari et al., Cancer Res. 1 (1992), 127).
  • Chari Chari et al., Cancer Res. 1 (1992), 127.
  • Preparation of humanized C242 (huC242) (Roguska et al., PNAS, 91 (1994), 969) has been previously described.
  • Antibody-drug conjugates were prepared as previously described (Liu et al., PNAS, 93 (1996), 8618). An average of 3.5 DM1 molecules was linked per antibody molecule.
  • BT062 is an antibody-drug conjugate composed of the cytotoxic maytansinoid drug, DM4, linked via disulfide bonds through a linker to the nBT062 chimerized monoclonal antibody.
  • Maytansinoids are anti-mitotics that inhibit tubulin polymerization and microtubule assembly (Remillard et al., Science 189 (1977), 1002).
  • Chemical and schematic representations of BT062 (nBT062-DM4) are shown in FIGS. 1 and 2 .
  • DM4 is prepared from the well known derivative maytansinol (Kupchan et al., J. Med. Chem., 21 (1978), 31). Maytansinol is prepared by reductive cleavage of the ester moiety of the microbial fermentation product, ansamitocin P3, with lithium trimethoxyaluminum hydride (see FIG. 3 ).
  • DM4 is synthesized by acylation of maytansinol with N-methyl-N-(4-methydithiopentanoyl)-L-alanine (DM4 side chain) in the presence of dicyclohexylcarbodiimide (DCC) and zinc chloride to give the disulfide-containing maytansinoid DM4-SMe.
  • DCC dicyclohexylcarbodiimide
  • zinc chloride zinc chloride
  • the DM4-SMe is reduced with dithiothreitol (DTT) to give the desired thiol-containing maytansinoid DM4 (see FIG. 4 for the DM4 process flow diagram).
  • nBT062-DM4 The procedure for the preparation of nBT062-DM4 is outlined in FIG. 5 .
  • the nBT062 antibody is modified with N-succinimidyl-4-(2-pyridyldithio) butyrate (SPDB linker) to introduce dithiopyridyl groups.
  • DM4 is mixed with the modified antibody at a concentration in excess of the equivalents of dithiopyridyl groups.
  • the BT062 conjugate forms by a disulfide exchange reaction between the thiol group of DM4 and the dithiopyridyl groups introduced into the antibody via the linker. Purification by chromatography and diafiltration removes the low molecular weight reactants (DM4) and reaction products (thiopyridine), as well as aggregates of conjugated antibody, to produce the bulk drug substance.
  • DM4 low molecular weight reactants
  • thiopyridine reaction products
  • OPM-2 cells are plasma cell leukemia cell lines showing highly expressing CD138.
  • OPM-2 cells were incubated with nBT062, nBT062-SPDB-DM4, nBT062-SPP-DM1 or nBT062-SMCC-DM1 at different concentrations (indicated in FIG. 6 ). The cells were washed and CD138-bound antibody or conjugates were detected using a fluorescence-labeled secondary antibody in FACS analysis. The mean fluorescence measured in these experiments was plotted against the antibody concentration.
  • CD138 + MOLP-8 cells were seeded in flat bottom plates at 3000 cells/well.
  • CD138 ⁇ BJAB control cells were seeded at 1000 cells/well.
  • the cells were treated with nBT062-SPDB-DM4, nBT062-SPP-DM1 or nBT062-SMCC-DM1 at different concentrations (indicated in FIG. 7 ) for five days.
  • WST reagent water-soluble tetrazolium salt, ROCHE
  • ROCHE manufacturer's instruction
  • the reagent was incubated for 7.5 h on MOLP-8 cells and for 2 h on BJAB cells. The fraction of surviving cells was calculated based on the optical densities measured in a microplate reader using standard procedures.
  • Binding of nBT062-SPDB-DM4, nBT062-SPP-DM1, nBT062-SMCC-DM1 or nBT062 was analyzed by FACS.
  • CD138 + OPM-2 as target cells were incubated with nBT062 or immunoconjugates and cell-bound molecules were detected using a fluorescence-labeled secondary antibody.
  • FIG. 6 the mean fluorescences as measure for the amount of cell bound antibody is plotted against different antibody or conjugate concentrations.
  • the results show, that nBT062-SPDB-DM4, nBT062-SPP-DM1 and nBT062-SMCC-DM1 show very similar binding characteristics.
  • the results strongly suggest that the binding characteristics of the unconjugated antibody is not affected by the conjugated toxins.
  • nBT062 To evaluate the importance of CD138 targeting on the anti-tumor activity of antibody-maytansinoid conjugates of a human chimeric version of the B-B4 antibody, nBT062, xenograft mouse experiments were performed. Two versions of nBT062-maytansinoid conjugates were prepared that may differ in the chemical stability of their disulfide linkages (nBT062-SPP-DM1 and nBT062-SPDB-DM4).
  • the anti-tumor activity of these antibody-drug conjugates was compared to the activity of the B-B4-SPP-DM1 conjugate (comprising the murine parental antibody), as well as unconjugated free maytansinoid (DM4), native unmodified nBT062 antibody, and a non-targeting (irrelevant) IgG1-maytansinoid conjugate.
  • the conjugates were evaluated in a CD138-positive xenograft model (MOLP-8) of human multiple myeloma in severe combined immunodeficient (SCID) mice.
  • mice subcutaneous tumors were established (female CB.17 SCID mice) by inoculation with MOLP-8 cell suspensions. Treatment with a single bolus intravenous injection was conducted when tumor volumes reached an average 113 mm 3 . Changes in tumor volume and body weight were monitored twice per week. Experiments were carried out over 68 days after tumor cell inoculation.
  • mice Female CB.17 SCID mice, five weeks old, were obtained from Charles River Laboratories.
  • MOLP-8 a human multiple myeloma cell line, was supplied from ATCC.
  • MOLP-8 cells which express the CD138 antigen on their cell surface and develop xenograft tumors in SCID mice, were maintained in RPMI-1640 medium supplemented with 4 mM L-glutamine (Biowhittaker, Walkersville, Md.), 10% fetal bovine serum (Hyclone, Logan, Utah) and 1% streptomycin/penicillin, at 37° C. in a humidified atmosphere that contained 5% CO 2 .
  • Each mouse was inoculated with 1 ⁇ 10 7 MOLP-8 cells subcutaneously into the area under the right shoulder.
  • the total volume was 0.2 ml per mouse, in which the ratio of serum-free medium to matrigel (BD Bioscience, Bedford, Mass.) was 1/1 (v/v).
  • the xenograft tumors Prior to treatment, the xenograft tumors were monitored daily and were allowed to become established. The tumor volume reached approximately 113 mm 3 about 11 days after tumor cell inoculation. Tumor take rate of CB.17 SCID mice was 100%.
  • mice were selected based on tumor volumes and body weights.
  • the tumor volume was in a range of 68.2 to 135.9 mm 3 .
  • the forty-two mice were randomly divided into seven groups (A-G) of six animals each based on tumor volume.
  • mice in Group A received 200 ⁇ l of PBS as vehicle control.
  • Each mouse in group B received 13.8 mg/kg of nBT062 naked antibody. This dose is equivalent to the amount of nBT062 antibody component in 250 ⁇ g/kg of linked maytansinoid. The ratio of molecular weights of maytansinoids to nBT062 antibody in a conjugate molecule is approximate 1/55.
  • Each mouse in Group C received 250 ⁇ g/kg of DM4.
  • Each mouse in Group D received 250 ⁇ g/kg of huC242-DM4.
  • Mice in groups E, F and G received 250 ⁇ g/kg of nBT062-SPDB-DM4, B-B4-SPP-DM1 and nBT062-SPP-DM1 each, respectively.
  • nBT062 antibody nBT062-SPDB-DM4 and nBT062-SPP-DM1 were diluted with sterile PBS to concentrations of 2 mg/ml, 28.1 ⁇ g/ml and 28.1 ⁇ g/ml, respectively, so that the injected volume for each mouse was between 120-220 ⁇ l.
  • MOLP-8 cells 1.5 ⁇ 10 7 cells per mouse
  • a 50:50 mixture of serum free media and matrigel were injected subcutaneously in the area under the right shoulder in 100 ⁇ l.
  • Tumor volumes reached about 80 mm 3 at day 11 and the mean of the controls was about 750 mm 3 at day 25, post cell inoculation.
  • the tumor doubling time was estimated to be 4.58 days.
  • An additional group (n 6) received 250 ⁇ g/kg nBT062-SMCC-DM1 in a repeated dosing (weekly for five weeks).
  • Tumor size was measured twice per week in three dimensions using the LabCat System (Tumor Measurement and Tracking, Alternative Programming Associated, Inc., Princeton, N.J.).
  • T d is the tumor doubling time, based on the median tumor volume in the control mice, and 3.32 is the number of cell doublings per log of cell growth.
  • the tumor growth in individual mice is shown in FIGS. 8 and 9 .
  • the mean (+/ ⁇ SD) tumor growth for each group is shown in FIG. 10 .
  • nBT062-SPDB-DM4 All three CD138-targeting conjugates, nBT062-SPDB-DM4, B-B4-SPP-DM1 and nBT062-SPP-DM1, at a dose of 250 ⁇ g/kg caused marked delay in tumor growth.
  • the DM4 conjugate nBT062-SPDB-DM4 was the most active one, while the nBT062-SPP-DM1 conjugate showed slightly increased activity as compared to its murine counterpart B-B4-SPP-DM1 ( FIG. 10 ).
  • mice show in addition that the anti-tumor activity obtained with B-B4-SPP-DM1 is more heterogeneously and therefore less predicable than that measure in mice treated with nBT062-SPP-DM1.
  • the other conjugate that uses nBT062 as targeting antibody nBT062-SPDB-DM4 behaved similar to nBT062-SPP-DM1.
  • nBT062-SPP-DM1 The immunoconjugate prepared from the human chimeric antibody, nBT062-SPP-DM1, gave slightly higher anti-tumor activity then the conjugate prepared from its murine counterpart, B-B4-SPP-DM1.
  • treatment with nBT062-SPP-DM1 and nBT062-SPDB-DM4 resulted in more homogenous responses in individual mice as compared to treatment with B-B4-SPP-DM1.
  • B-B4-SPP-DM1 The high binding variation of B-B4-SPP-DM1 explained that the measurement of the median tumor volume (+/ ⁇ SD) of MOLP-8 human multiple myeloma xenografts in CB.17 SCID mice over time (days) post-inoculation actually provided for relatively better results for B-B4-SPP-DM1 than for nBT062-SPP-DM1 (data not shown).
  • This feature of immunoconjugates using nBT062 as a targeting antibody seems to be beneficial especially for therapeutic use of the conjugates.
  • mice eighty-five mice were inoculated with MOLP-8 cells (1.5 ⁇ 10 7 cells/mouse) subcutaneously in the right shoulder. Tumor take rate was 100%.
  • a median tumor volume of 750 mm 3 in the PBS-treated animals was reached on day 25.
  • Tumor doubling time determined by the best-fit linear regression curve fit on a log-linear plot of control tumor growth was 4.58 days.

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Cited By (4)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US10973920B2 (en) 2014-06-30 2021-04-13 Glykos Finland Oy Saccharide derivative of a toxic payload and antibody conjugates thereof
US11945868B2 (en) 2017-10-02 2024-04-02 Visterra, Inc. Antibody molecules to CD138 and uses thereof
US11944644B2 (en) 2017-12-05 2024-04-02 The Medical Research Infrastructure And Health Services Fund Of The Tel Aviv Medical Center T-cells comprising anti-CD38 and anti-CD138 chimeric antigen receptors and uses thereof
WO2024102954A1 (en) 2022-11-10 2024-05-16 Massachusetts Institute Of Technology Activation induced clipping system (aics)

Families Citing this family (79)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
AU2004224925C1 (en) * 2004-08-30 2011-07-21 Biotest Ag Immunoconjugates targeting syndecan-1 expressing cells and use thereof
MX2010007101A (es) * 2007-12-26 2011-07-01 Biotest Ag Metodos y agentes para mejorar el reconocimiento de celulas de tumor que expresan cd138.
BRPI0821449A2 (pt) * 2007-12-26 2015-06-16 Biotest Ag Imunoconjugado, métodos para tratar mieloma múltiplo em um indíviduo, para dispensar medicamento mediado por imunoconjugado, para inibir, atrasar e/ou evitar o desenvolvimento de um tumor e/ou dispensar células tumorais malignas em um paciente em necessidade do mesmo, para tratar um indíviduo tendo uma condição e opara diminuir uma quantidade de células em contato direto ou indireto com as imunoconjugado, método para tratar mieloma múltiplo em um indivíduo, para dispensar medicamento mediado por imunoconjugado, para inibir, atrasar e/ou evitar o desenvolvimento de células tumorais em uma cultura celular, para inibir, atrasar e/ou evitar o desenvolvimento de um tumor e/ou dispensar células tumorais malignas em um paciente em necessidade do mesmo, para tratar um indivíduo tendo uma condição e para diminuir uma quantidade de células em contato direto ou indireto com as células tumorais, composição farmacêutica, e, kit.
PL2238168T3 (pl) 2007-12-26 2014-11-28 Biotest Ag Środki które mają za cel CD138 i ich zastosowania
RU2015128833A (ru) * 2009-05-06 2015-11-10 Биотест Аг Применения иммуноконъюгатов, мишенью которых является cd138
AU2013201618B2 (en) * 2009-05-06 2016-06-02 Biotest Ag Uses of immunoconjugates targeting CD138
CA2833477A1 (en) 2011-04-21 2012-10-26 Seattle Genetics, Inc. Novel binder-drug conjugates (adcs) and their use
KR102096224B1 (ko) 2011-10-28 2020-04-03 테바 파마슈티컬즈 오스트레일리아 피티와이 엘티디 폴리펩티드 구축물 및 이의 용도
US10117932B2 (en) 2011-12-08 2018-11-06 Biotest Ag Uses of immunoconjugates targeting CD138
RS53818B1 (en) 2012-10-12 2015-06-30 Spirogen Sàrl PIROLOBENZODIAZEPINI I NJIHOVI conjugated
CN103103197A (zh) * 2013-01-30 2013-05-15 百奇生物科技(苏州)有限公司 抗cd138单克隆抗体可变区序列及其制备方法和应用
WO2014138704A1 (en) * 2013-03-07 2014-09-12 Baylor College Of Medicine Targeting cd138 in cancer
BR112015023333A8 (pt) 2013-03-13 2018-04-17 Medimmune Ltd pirrolbenzodiazepinas e conjugados dos mesmos
US11117975B2 (en) 2013-04-29 2021-09-14 Teva Pharmaceuticals Australia Pty Ltd Anti-CD38 antibodies and fusions to attenuated interferon alpha-2B
MX370377B (es) 2013-04-29 2019-12-11 Teva Pharmaceuticals Australia Pty Ltd Anticuerpos anti-cd38 y fusiones con interferón alfa-2b atenuado.
DK3086814T3 (da) 2013-12-23 2020-09-14 Bayer Pharma AG Binder-konjugater (adcs) med ksp-inhibitorer
UA119352C2 (uk) 2014-05-01 2019-06-10 Тева Фармасьютикалз Острейліа Пті Лтд Комбінація леналідоміду або помалідоміду і конструкції анти-cd38 антитіло-атенуйований інтерферон альфа-2b та спосіб лікування суб'єкта, який має cd38-експресуючу пухлину
EP3169773B1 (en) 2014-07-15 2023-07-12 Juno Therapeutics, Inc. Engineered cells for adoptive cell therapy
US10648554B2 (en) 2014-09-02 2020-05-12 Polaris Industries Inc. Continuously variable transmission
CN106687141A (zh) 2014-09-10 2017-05-17 麦迪穆有限责任公司 吡咯并苯并二氮杂卓及其缀合物
JP6730271B2 (ja) 2014-10-29 2020-07-29 テバ・ファーマシューティカルズ・オーストラリア・ピーティワイ・リミテッド インターフェロンα2Bバリアント
TWI588259B (zh) * 2015-03-06 2017-06-21 Methods for screening antigen-specific fusion tumor cells
PE20180610A1 (es) 2015-06-22 2018-04-09 Bayer Pharma AG CONJUGADOS DE LIGADOR-PRINCIPIO ACTIVO (ADCs) Y CONJUGADOS DE LIGADOR-PROFARMACO (APDCs) CON GRUPOS ENZIMATICAMENTE ESCINDIBLES
MA42895A (fr) 2015-07-15 2018-05-23 Juno Therapeutics Inc Cellules modifiées pour thérapie cellulaire adoptive
RU2611685C2 (ru) * 2015-07-20 2017-02-28 Илья Владимирович Духовлинов Гуманизированное моноклональное антитело, специфичное к синдекану-1
WO2017060322A2 (en) 2015-10-10 2017-04-13 Bayer Pharma Aktiengesellschaft Ptefb-inhibitor-adc
JP7251981B2 (ja) 2016-03-24 2023-04-04 バイエル ファーマ アクチエンゲゼルシャフト 酵素開裂基を有する細胞毒性活性剤のプロドラッグ
JP7022707B2 (ja) 2016-06-15 2022-02-18 バイエル・ファルマ・アクティエンゲゼルシャフト Ksp阻害剤および抗cd123抗体を含む特異的抗体-薬物-コンジュゲート(adc)
JP2019534882A (ja) 2016-10-11 2019-12-05 メドイミューン・リミテッドMedImmune Limited 免疫介在性療法薬を有する抗体−薬物コンジュゲート
WO2018114578A1 (de) 2016-12-21 2018-06-28 Bayer Pharma Aktiengesellschaft Binder-wirkstoff-konjugate (adcs) mit enzymatisch spaltbaren gruppen
CA3047522A1 (en) 2016-12-21 2018-06-28 Bayer Pharma Aktiengesellschaft Specific antibody drug conjugates (adcs) having ksp inhibitors
KR20190099250A (ko) 2016-12-21 2019-08-26 바이엘 악티엔게젤샤프트 효소적으로 절단가능한 기를 갖는 세포독성 활성제의 전구약물
US10697532B2 (en) 2016-12-22 2020-06-30 Polaris Industries Inc. Housing for a transmission
US11242403B2 (en) 2017-04-26 2022-02-08 Mitsubishi Tanabe Pharma Corporation Syndecan-1 (CD138) binding agents and uses thereof
JP2020530097A (ja) * 2017-05-05 2020-10-15 ユニバーシティ オブ テクノロジー,シドニー 癌の予後診断(prognosis)のための方法
EP3538645B1 (en) 2017-06-20 2021-01-20 Institut Curie Immune cells defective for suv39h1
US11066475B2 (en) 2017-11-01 2021-07-20 Juno Therapeutics, Inc. Chimeric antigen receptors specific for B-cell maturation antigen and encoding polynucleotides
BR112020008565A2 (pt) 2017-11-01 2020-10-20 Juno Therapeutics Inc processo para a produção de uma composição de célula t
WO2019089848A1 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Methods associated with tumor burden for assessing response to a cell therapy
AU2018358067A1 (en) 2017-11-01 2020-05-07 Juno Therapeutics, Inc. Antibodies and chimeric antigen receptors specific for B-cell maturation antigen
WO2019089858A2 (en) 2017-11-01 2019-05-09 Juno Therapeutics, Inc. Methods of assessing or monitoring a response to a cell therapy
EP3704230B1 (en) 2017-11-01 2024-10-23 Juno Therapeutics, Inc. Process for generating therapeutic compositions of engineered cells
BR112020011215A2 (pt) 2017-12-08 2020-11-17 Juno Therapeutics Inc processo para a produção de uma composição de células t modificadas
EP3720480A2 (en) 2017-12-08 2020-10-14 Juno Therapeutics, Inc. Phenotypic markers for cell therapy and related methods
EA202091407A1 (ru) 2017-12-08 2020-10-20 Джуно Терапьютикс, Инк. Состав бессывороточной среды для культивирования клеток и способы его применения
US11649889B2 (en) 2018-03-19 2023-05-16 Polaris Industries Inc. Continuously variable transmission
US11543005B2 (en) 2018-03-19 2023-01-03 Polaris Industries Inc. Electronic CVT with friction clutch
KR20210016562A (ko) 2018-05-23 2021-02-16 에이디씨 테라퓨틱스 에스에이 분자 애쥬번트
KR20210059715A (ko) 2018-08-09 2021-05-25 주노 쎄러퓨티크스 인코퍼레이티드 통합된 핵산 평가 방법
JP2022506598A (ja) 2018-11-01 2022-01-17 ジュノー セラピューティクス インコーポレイテッド Gタンパク質共役受容体クラスcグループ5メンバーd(gprc5d)に特異的なキメラ抗原受容体
JP7510413B2 (ja) 2018-11-01 2024-07-03 ジュノー セラピューティクス インコーポレイテッド B細胞成熟抗原に特異的なキメラ抗原受容体を使用する処置方法
KR20220016475A (ko) 2019-05-01 2022-02-09 주노 쎄러퓨티크스 인코퍼레이티드 변형된 tgfbr2 유전자 좌에서 재조합 수용체를 발현하는 세포, 관련 폴리뉴클레오티드 및 방법
JP2022531577A (ja) 2019-05-01 2022-07-07 ジュノー セラピューティクス インコーポレイテッド 改変されたcd247遺伝子座からキメラ受容体を発現する細胞、関連ポリヌクレオチド、および方法
CA3142021A1 (en) * 2019-06-17 2020-12-24 Visterra, Inc. Humanized antibody molecules to cd138 and uses thereof
BR112022001148A2 (pt) 2019-07-23 2022-03-15 Inst Nat Sante Rech Med Células imunes modificadas, composição farmacêutica, kit, uso de uma célula imune modificada e invenção de produto
KR102287180B1 (ko) 2019-10-01 2021-08-09 충북대학교 산학협력단 Cd138에 특이적으로 결합하는 키메릭 항원 수용체, 이를 발현하는 면역세포 및 이의 항암 용도
US20230149462A1 (en) 2020-04-10 2023-05-18 Juno Therapeutics, Inc. Methods and uses related to cell therapy engineered with a chimeric antigen receptor targeting b-cell maturation antigen
WO2021231657A1 (en) 2020-05-13 2021-11-18 Juno Therapeutics, Inc. Methods of identifying features associated with clinical response and uses thereof
WO2021260186A1 (en) 2020-06-26 2021-12-30 Juno Therapeutics Gmbh Engineered t cells conditionally expressing a recombinant receptor, related polynucleotides and methods
JP2023535501A (ja) 2020-07-30 2023-08-17 アンスティテュ・クリー Socs1に欠陥のある免疫細胞
US20230372528A1 (en) 2020-10-16 2023-11-23 University Of Georgia Research Foundation, Inc. Glycoconjugates
US20230398148A1 (en) 2020-11-04 2023-12-14 Juno Therapeutics, Inc. Cells expressing a chimeric receptor from a modified invariant cd3 immunoglobulin superfamily chain locus and related polynucleotides and methods
GB202102396D0 (en) 2021-02-19 2021-04-07 Adc Therapeutics Sa Molecular adjuvant
US20240108654A1 (en) 2021-03-03 2024-04-04 Juno Therapeutics, Inc. Combination of a t cell therapy and a dgk inhibitor
JP2024517863A (ja) 2021-05-06 2024-04-23 ジュノ・セラピューティクス・ゲゼルシャフト・ミット・ベシュレンクテル・ハフツング 細胞を刺激し、形質導入する方法
US20240269282A1 (en) 2021-05-10 2024-08-15 Institut Curie Methods for the Treatment of Cancer, Inflammatory Diseases and Autoimmune Diseases
WO2022248602A1 (en) 2021-05-25 2022-12-01 Institut Curie Myeloid cells overexpressing bcl2
EP4456910A1 (en) 2021-12-28 2024-11-06 Mnemo Therapeutics Immune cells with inactivated suv39h1 and modified tcr
WO2023147515A1 (en) 2022-01-28 2023-08-03 Juno Therapeutics, Inc. Methods of manufacturing cellular compositions
WO2023159182A1 (en) 2022-02-18 2023-08-24 Rakuten Medical, Inc. Anti-programmed death-ligand 1 (pd-l1) antibody molecules, encoding polynucleotides, and methods of use
WO2023187024A1 (en) 2022-03-31 2023-10-05 Institut Curie Modified rela protein for inducing interferon expression and engineered immune cells with improved interferon expression
WO2023213969A1 (en) 2022-05-05 2023-11-09 Juno Therapeutics Gmbh Viral-binding protein and related reagents, articles, and methods of use
WO2023220655A1 (en) 2022-05-11 2023-11-16 Celgene Corporation Methods to overcome drug resistance by re-sensitizing cancer cells to treatment with a prior therapy via treatment with a t cell therapy
WO2023230581A1 (en) 2022-05-25 2023-11-30 Celgene Corporation Methods of manufacturing t cell therapies
WO2023230548A1 (en) 2022-05-25 2023-11-30 Celgene Corporation Method for predicting response to a t cell therapy
WO2024054944A1 (en) 2022-09-08 2024-03-14 Juno Therapeutics, Inc. Combination of a t cell therapy and continuous or intermittent dgk inhibitor dosing
WO2024100604A1 (en) 2022-11-09 2024-05-16 Juno Therapeutics Gmbh Methods for manufacturing engineered immune cells
WO2024124132A1 (en) 2022-12-09 2024-06-13 Juno Therapeutics, Inc. Machine learning methods for predicting cell phenotype using holographic imaging
WO2024161021A1 (en) 2023-02-03 2024-08-08 Juno Therapeutics Gmbh Methods for non-viral manufacturing of engineered immune cells

Citations (99)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3896111A (en) 1973-02-20 1975-07-22 Research Corp Ansa macrolides
US4137230A (en) 1977-11-14 1979-01-30 Takeda Chemical Industries, Ltd. Method for the production of maytansinoids
US4151042A (en) 1977-03-31 1979-04-24 Takeda Chemical Industries, Ltd. Method for producing maytansinol and its derivatives
US4169888A (en) 1977-10-17 1979-10-02 The Upjohn Company Composition of matter and process
US4248870A (en) 1978-10-27 1981-02-03 Takeda Chemical Industries, Ltd. Maytansinoids and use
US4256746A (en) 1978-11-14 1981-03-17 Takeda Chemical Industries Dechloromaytansinoids, their pharmaceutical compositions and method of use
US4260608A (en) 1978-11-14 1981-04-07 Takeda Chemical Industries, Ltd. Maytansinoids, pharmaceutical compositions thereof and methods of use thereof
US4265814A (en) 1978-03-24 1981-05-05 Takeda Chemical Industries Matansinol 3-n-hexadecanoate
US4294757A (en) 1979-01-31 1981-10-13 Takeda Chemical Industries, Ltd 20-O-Acylmaytansinoids
US4307016A (en) 1978-03-24 1981-12-22 Takeda Chemical Industries, Ltd. Demethyl maytansinoids
US4308268A (en) 1979-06-11 1981-12-29 Takeda Chemical Industries, Ltd. Maytansinoids, pharmaceutical compositions thereof and method of use thereof
US4308269A (en) 1979-06-11 1981-12-29 Takeda Chemical Industries, Ltd. Maytansinoids, pharmaceutical compositions thereof and method of use thereof
US4309428A (en) 1979-07-30 1982-01-05 Takeda Chemical Industries, Ltd. Maytansinoids
US4313946A (en) 1981-01-27 1982-02-02 The United States Of America As Represented By The Secretary Of Agriculture Chemotherapeutically active maytansinoids from Trewia nudiflora
US4315929A (en) 1981-01-27 1982-02-16 The United States Of America As Represented By The Secretary Of Agriculture Method of controlling the European corn borer with trewiasine
US4317821A (en) 1979-06-08 1982-03-02 Takeda Chemical Industries, Ltd. Maytansinoids, their use and pharmaceutical compositions thereof
US4322348A (en) 1979-06-05 1982-03-30 Takeda Chemical Industries, Ltd. Maytansinoids
US4331598A (en) 1979-09-19 1982-05-25 Takeda Chemical Industries, Ltd. Maytansinoids
US4362663A (en) 1979-09-21 1982-12-07 Takeda Chemical Industries, Ltd. Maytansinoid compound
US4364866A (en) 1979-09-21 1982-12-21 Takeda Chemical Industries, Ltd. Maytansinoids
US4371533A (en) 1980-10-08 1983-02-01 Takeda Chemical Industries, Ltd. 4,5-Deoxymaytansinoids, their use and pharmaceutical compositions thereof
US4418064A (en) 1982-09-29 1983-11-29 The United States Of America As Represented By The Secretary Of Agriculture Chemotherapeutically active maytansinoids: treflorine, trenudine, and N-methyltrenudone
US4424219A (en) 1981-05-20 1984-01-03 Takeda Chemical Industries, Ltd. 9-Thiomaytansinoids and their pharmaceutical compositions and use
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
WO1988002594A2 (en) 1986-10-09 1988-04-21 Neorx Corporation Methods for improved targeting of antibody, antibody fragments, hormones and other targeting agents, and conjugates thereof
US4761111A (en) 1981-09-18 1988-08-02 Brown Andrew M Automobile lifting and towing equipment
WO1991009967A1 (en) 1989-12-21 1991-07-11 Celltech Limited Humanised antibodies
WO1991010741A1 (en) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation of xenogeneic antibodies
US5053394A (en) 1988-09-21 1991-10-01 American Cyanamid Company Targeted forms of methyltrithio antitumor agents
EP0519596A1 (en) 1991-05-17 1992-12-23 Merck & Co. Inc. A method for reducing the immunogenicity of antibody variable domains
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
EP0592106A1 (en) 1992-09-09 1994-04-13 Immunogen Inc Resurfacing of rodent antibodies
US5367086A (en) 1992-03-13 1994-11-22 University Of Florida Process for the preparation of taxol and 10-deacetyltaxol
US5475092A (en) 1992-03-25 1995-12-12 Immunogen Inc. Cell binding agent conjugates of analogues and derivatives of CC-1065
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1997011971A1 (en) * 1995-09-28 1997-04-03 Alexion Pharmaceuticals, Inc. Porcine cell interaction proteins
US5703247A (en) 1993-03-11 1997-12-30 Virginia Tech Intellectual Properties, Inc. 2-Debenzoyl-2-acyl taxol derivatives and methods for making same
US5705508A (en) 1993-03-26 1998-01-06 The Research Foundation Of State University Of New York Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment
US5712374A (en) 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US5739350A (en) 1990-04-25 1998-04-14 Pharmacia & Upjohn Company CC-1065 analogs
WO1998016654A1 (en) 1996-10-11 1998-04-23 Japan Tobacco, Inc. Production of a multimeric protein by cell fusion method
US5763477A (en) 1994-07-22 1998-06-09 Dr. Reddy's Research Foundation Taxane derivatives from 14-β-hydroxy-10 deacetylbaccatin III
US5773001A (en) 1994-06-03 1998-06-30 American Cyanamid Company Conjugates of methyltrithio antitumor agents and intermediates for their synthesis
WO1998024893A3 (en) 1996-12-03 1998-08-20 Abgenix Inc TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
WO1998046645A2 (en) 1997-04-14 1998-10-22 Micromet Gesellschaft Für Biomedizinische Forschung Mbh Method for the production of antihuman antigen receptors and uses thereof
US5831012A (en) 1994-01-14 1998-11-03 Pharmacia & Upjohn Aktiebolag Bacterial receptor structures
WO1998050433A2 (en) 1997-05-05 1998-11-12 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
US5892063A (en) 1995-03-10 1999-04-06 Hauser, Inc. Cephalomannine epoxide, its analogues and a method for preparing the same
US5998656A (en) 1991-09-23 1999-12-07 Florida State University C10 tricyclic taxanes
US6001358A (en) * 1995-11-07 1999-12-14 Idec Pharmaceuticals Corporation Humanized antibodies to human gp39, compositions containing thereof
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
US6080777A (en) 1992-01-31 2000-06-27 The Trustees Of Columbia University In The City Of New York Taxol as a radiation sensitizer
US6087362A (en) 1999-03-16 2000-07-11 Pentech Pharmaceuticals, Inc. Apomorphine and sildenafil composition
US6333410B1 (en) 2000-08-18 2001-12-25 Immunogen, Inc. Process for the preparation and purification of thiol-containing maytansinoids
US20020006379A1 (en) 1998-06-22 2002-01-17 Hansen Hans J. Production and use of novel peptide-based agents for use with bi-specific antibodies
US6340701B1 (en) 1999-11-24 2002-01-22 Immunogen Inc Cytotoxic agents comprising taxanes and their therapeutic use
WO2002016602A2 (en) 2000-08-24 2002-02-28 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
WO2003011878A2 (en) 2001-08-03 2003-02-13 Glycart Biotechnology Ag Antibody glycosylation variants having increased antibody-dependent cellular cytotoxicity
US6534660B1 (en) 2002-04-05 2003-03-18 Immunogen, Inc. CC-1065 analog synthesis
US20030055226A1 (en) 2001-05-31 2003-03-20 Immunogen, Inc. Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
US6596757B1 (en) 2002-05-14 2003-07-22 Immunogen Inc. Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use
US20040002587A1 (en) * 2002-02-20 2004-01-01 Watkins Jeffry D. Fc region variants
US20040024049A1 (en) 2002-08-02 2004-02-05 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
US6716821B2 (en) 2001-12-21 2004-04-06 Immunogen Inc. Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same
US20040082764A1 (en) 2002-05-02 2004-04-29 Wyeth Holdings Corporation Calicheamicin derivative-carrier conjugates
US6740734B1 (en) 1994-01-14 2004-05-25 Biovitrum Ab Bacterial receptor structures
US6756397B2 (en) 2002-04-05 2004-06-29 Immunogen, Inc. Prodrugs of CC-1065 analogs
US20040126379A1 (en) 2002-08-21 2004-07-01 Boehringer Ingelheim International Gmbh Compositions and methods for treating cancer using cytotoxic CD44 antibody immunoconjugates and chemotherapeutic agents
WO2004099379A2 (en) 2003-05-02 2004-11-18 Health Research, Inc. Use of jag2 expression in diagnosis of plasma cell disorders
US20040235840A1 (en) 2003-05-20 2004-11-25 Immunogen, Inc. Cytotoxic agents comprising new maytansinoids
US20040241817A1 (en) 2003-01-22 2004-12-02 Glycart Biotechnology Ag Fusion constructs and use of same to produce antibodies with increased Fc receptor binding affinity and effector function
US20050123549A1 (en) 2003-07-21 2005-06-09 Immunogen Inc. CA6 antigen-specific cytotoxic conjugate and methods of using the same
WO2006008548A2 (en) 2004-07-22 2006-01-26 Erasmus University Medical Centre Rotterdam Binding molecules
US20060024298A1 (en) 2002-09-27 2006-02-02 Xencor, Inc. Optimized Fc variants
CA2486285A1 (en) 2004-08-30 2006-02-28 Viktor S. Goldmakher Immunoconjugates targeting syndecan-1 expressing cells and use thereof
WO2006099875A1 (en) 2005-03-23 2006-09-28 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
WO2006110466A2 (en) 2005-04-07 2006-10-19 Novartis Vaccines And Diagnostics Inc. CANCER-RELATED GENES (PTPϵ)
US20060233814A1 (en) 2005-04-15 2006-10-19 Immunogen Inc. Elimination of heterogeneous or mixed cell population in tumors
US20070054332A1 (en) 2005-08-10 2007-03-08 Alan Rapraeger Syndecan 1 ectodomain inhibits cancer
JP2007077155A (ja) 2000-08-24 2007-03-29 Genentech Inc 腫瘍の診断と治療のための組成物と方法
WO2007066109A1 (en) 2005-12-06 2007-06-14 Domantis Limited Bispecific ligands with binding specificity to cell surface targets and methods of use therefor
US20070148163A1 (en) 2003-12-25 2007-06-28 Kirin Beer Kabushiki Kaisha Mutants of anti-cd40 antibody
WO2007144046A2 (de) 2006-05-03 2007-12-21 Elke Pogge Von Strandmann Mittel zur behandlung von malignen erkrankungen
US20080063635A1 (en) 2004-09-22 2008-03-13 Kirin Beer Kabushiki Kaisha Stabilized Human Igg4 Antibodies
US20080171040A1 (en) 2004-06-01 2008-07-17 Genentech, Inc. Antibody-drug conjugates and methods
EP2006381A1 (en) 2006-03-31 2008-12-24 Chugai Seiyaku Kabushiki Kaisha Method for control of blood kinetics of antibody
US20090087429A1 (en) 2000-03-21 2009-04-02 Jian Chen IL-17 homologous polypeptides and therapeutic uses thereof
US20090169570A1 (en) 2007-12-26 2009-07-02 Benjamin Daelken Methods and agents for improving targeting of cd138 expressing tumor cells
US20090175863A1 (en) 2007-12-26 2009-07-09 Elmar Kraus Agents targeting cd138 and uses thereof
US20090181038A1 (en) 2007-12-26 2009-07-16 Gregor Schulz Method of decreasing cytotoxic side-effects and improving efficacy of immunoconjugates
US20110123554A1 (en) 2009-05-06 2011-05-26 Frank Osterroth Uses of immunoconjugates targeting cd138

Family Cites Families (3)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US4563304A (en) 1981-02-27 1986-01-07 Pharmacia Fine Chemicals Ab Pyridine compounds modifying proteins, polypeptides or polysaccharides
US4716111A (en) 1982-08-11 1987-12-29 Trustees Of Boston University Process for producing human antibodies
US20050027128A1 (en) * 2003-07-30 2005-02-03 Robbins Timothy A. Substituted thiazoles

Patent Citations (119)

* Cited by examiner, † Cited by third party
Publication number Priority date Publication date Assignee Title
US3896111A (en) 1973-02-20 1975-07-22 Research Corp Ansa macrolides
US4151042A (en) 1977-03-31 1979-04-24 Takeda Chemical Industries, Ltd. Method for producing maytansinol and its derivatives
US4169888A (en) 1977-10-17 1979-10-02 The Upjohn Company Composition of matter and process
US4137230A (en) 1977-11-14 1979-01-30 Takeda Chemical Industries, Ltd. Method for the production of maytansinoids
US4307016A (en) 1978-03-24 1981-12-22 Takeda Chemical Industries, Ltd. Demethyl maytansinoids
US4361650A (en) 1978-03-24 1982-11-30 Takeda Chemical Industries, Ltd. Fermentation process of preparing demethyl maytansinoids
US4265814A (en) 1978-03-24 1981-05-05 Takeda Chemical Industries Matansinol 3-n-hexadecanoate
US4248870A (en) 1978-10-27 1981-02-03 Takeda Chemical Industries, Ltd. Maytansinoids and use
US4260608A (en) 1978-11-14 1981-04-07 Takeda Chemical Industries, Ltd. Maytansinoids, pharmaceutical compositions thereof and methods of use thereof
US4256746A (en) 1978-11-14 1981-03-17 Takeda Chemical Industries Dechloromaytansinoids, their pharmaceutical compositions and method of use
US4294757A (en) 1979-01-31 1981-10-13 Takeda Chemical Industries, Ltd 20-O-Acylmaytansinoids
US4322348A (en) 1979-06-05 1982-03-30 Takeda Chemical Industries, Ltd. Maytansinoids
US4317821A (en) 1979-06-08 1982-03-02 Takeda Chemical Industries, Ltd. Maytansinoids, their use and pharmaceutical compositions thereof
US4308268A (en) 1979-06-11 1981-12-29 Takeda Chemical Industries, Ltd. Maytansinoids, pharmaceutical compositions thereof and method of use thereof
US4308269A (en) 1979-06-11 1981-12-29 Takeda Chemical Industries, Ltd. Maytansinoids, pharmaceutical compositions thereof and method of use thereof
US4309428A (en) 1979-07-30 1982-01-05 Takeda Chemical Industries, Ltd. Maytansinoids
US4331598A (en) 1979-09-19 1982-05-25 Takeda Chemical Industries, Ltd. Maytansinoids
US4364866A (en) 1979-09-21 1982-12-21 Takeda Chemical Industries, Ltd. Maytansinoids
US4362663A (en) 1979-09-21 1982-12-07 Takeda Chemical Industries, Ltd. Maytansinoid compound
US4444887A (en) 1979-12-10 1984-04-24 Sloan-Kettering Institute Process for making human antibody producing B-lymphocytes
US4371533A (en) 1980-10-08 1983-02-01 Takeda Chemical Industries, Ltd. 4,5-Deoxymaytansinoids, their use and pharmaceutical compositions thereof
US4315929A (en) 1981-01-27 1982-02-16 The United States Of America As Represented By The Secretary Of Agriculture Method of controlling the European corn borer with trewiasine
US4313946A (en) 1981-01-27 1982-02-02 The United States Of America As Represented By The Secretary Of Agriculture Chemotherapeutically active maytansinoids from Trewia nudiflora
US4424219A (en) 1981-05-20 1984-01-03 Takeda Chemical Industries, Ltd. 9-Thiomaytansinoids and their pharmaceutical compositions and use
US4761111A (en) 1981-09-18 1988-08-02 Brown Andrew M Automobile lifting and towing equipment
US4418064A (en) 1982-09-29 1983-11-29 The United States Of America As Represented By The Secretary Of Agriculture Chemotherapeutically active maytansinoids: treflorine, trenudine, and N-methyltrenudone
EP0239400A2 (en) 1986-03-27 1987-09-30 Medical Research Council Recombinant antibodies and methods for their production
WO1988002594A2 (en) 1986-10-09 1988-04-21 Neorx Corporation Methods for improved targeting of antibody, antibody fragments, hormones and other targeting agents, and conjugates thereof
US5053394A (en) 1988-09-21 1991-10-01 American Cyanamid Company Targeted forms of methyltrithio antitumor agents
US5530101A (en) 1988-12-28 1996-06-25 Protein Design Labs, Inc. Humanized immunoglobulins
US5585089A (en) 1988-12-28 1996-12-17 Protein Design Labs, Inc. Humanized immunoglobulins
US5208020A (en) 1989-10-25 1993-05-04 Immunogen Inc. Cytotoxic agents comprising maytansinoids and their therapeutic use
WO1991009967A1 (en) 1989-12-21 1991-07-11 Celltech Limited Humanised antibodies
WO1991010741A1 (en) 1990-01-12 1991-07-25 Cell Genesys, Inc. Generation of xenogeneic antibodies
US5739350A (en) 1990-04-25 1998-04-14 Pharmacia & Upjohn Company CC-1065 analogs
US5814318A (en) 1990-08-29 1998-09-29 Genpharm International Inc. Transgenic non-human animals for producing heterologous antibodies
US5545806A (en) 1990-08-29 1996-08-13 Genpharm International, Inc. Ransgenic non-human animals for producing heterologous antibodies
EP0519596A1 (en) 1991-05-17 1992-12-23 Merck & Co. Inc. A method for reducing the immunogenicity of antibody variable domains
US6407213B1 (en) 1991-06-14 2002-06-18 Genentech, Inc. Method for making humanized antibodies
US5998656A (en) 1991-09-23 1999-12-07 Florida State University C10 tricyclic taxanes
US5565332A (en) 1991-09-23 1996-10-15 Medical Research Council Production of chimeric antibodies - a combinatorial approach
US6080777A (en) 1992-01-31 2000-06-27 The Trustees Of Columbia University In The City Of New York Taxol as a radiation sensitizer
US5367086A (en) 1992-03-13 1994-11-22 University Of Florida Process for the preparation of taxol and 10-deacetyltaxol
US5585499A (en) 1992-03-25 1996-12-17 Immunogen Inc. Cyclopropylbenzindole-containing cytotoxic drugs
US5475092A (en) 1992-03-25 1995-12-12 Immunogen Inc. Cell binding agent conjugates of analogues and derivatives of CC-1065
US5846545A (en) 1992-03-25 1998-12-08 Immunogen, Inc. Targeted delivery of cyclopropylbenzindole-containing cytotoxic drugs
US6005079A (en) 1992-08-21 1999-12-21 Vrije Universiteit Brussels Immunoglobulins devoid of light chains
US5639641A (en) 1992-09-09 1997-06-17 Immunogen Inc. Resurfacing of rodent antibodies
EP0592106A1 (en) 1992-09-09 1994-04-13 Immunogen Inc Resurfacing of rodent antibodies
US5703247A (en) 1993-03-11 1997-12-30 Virginia Tech Intellectual Properties, Inc. 2-Debenzoyl-2-acyl taxol derivatives and methods for making same
US6002023A (en) 1993-03-11 1999-12-14 Virginia Tech Intellectural Properties, Inc. 2-debenzoyl-2-acyl taxol derivatives and method for making same
US5705508A (en) 1993-03-26 1998-01-06 The Research Foundation Of State University Of New York Anti-tumor compounds, pharmaceutical compositions, methods for preparation thereof and for treatment
US6534628B1 (en) 1994-01-14 2003-03-18 Biovitrum Ab Bacterial receptor structures
US6740734B1 (en) 1994-01-14 2004-05-25 Biovitrum Ab Bacterial receptor structures
US5831012A (en) 1994-01-14 1998-11-03 Pharmacia & Upjohn Aktiebolag Bacterial receptor structures
US5877296A (en) 1994-06-03 1999-03-02 American Cyanamid Company Process for preparing conjugates of methyltrithio antitumor agents
US5773001A (en) 1994-06-03 1998-06-30 American Cyanamid Company Conjugates of methyltrithio antitumor agents and intermediates for their synthesis
US5763477A (en) 1994-07-22 1998-06-09 Dr. Reddy's Research Foundation Taxane derivatives from 14-β-hydroxy-10 deacetylbaccatin III
US5892063A (en) 1995-03-10 1999-04-06 Hauser, Inc. Cephalomannine epoxide, its analogues and a method for preparing the same
WO1996033735A1 (en) 1995-04-27 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
WO1996034096A1 (en) 1995-04-28 1996-10-31 Abgenix, Inc. Human antibodies derived from immunized xenomice
US5714586A (en) 1995-06-07 1998-02-03 American Cyanamid Company Methods for the preparation of monomeric calicheamicin derivative/carrier conjugates
US5712374A (en) 1995-06-07 1998-01-27 American Cyanamid Company Method for the preparation of substantiallly monomeric calicheamicin derivative/carrier conjugates
WO1997011971A1 (en) * 1995-09-28 1997-04-03 Alexion Pharmaceuticals, Inc. Porcine cell interaction proteins
US6001358A (en) * 1995-11-07 1999-12-14 Idec Pharmaceuticals Corporation Humanized antibodies to human gp39, compositions containing thereof
WO1998016654A1 (en) 1996-10-11 1998-04-23 Japan Tobacco, Inc. Production of a multimeric protein by cell fusion method
WO1998024893A3 (en) 1996-12-03 1998-08-20 Abgenix Inc TRANSGENIC MAMMALS HAVING HUMAN IG LOCI INCLUDING PLURAL VH AND Vλ REGIONS AND ANTIBODIES PRODUCED THEREFROM
WO1998046645A2 (en) 1997-04-14 1998-10-22 Micromet Gesellschaft Für Biomedizinische Forschung Mbh Method for the production of antihuman antigen receptors and uses thereof
WO1998050433A2 (en) 1997-05-05 1998-11-12 Abgenix, Inc. Human monoclonal antibodies to epidermal growth factor receptor
US20050272128A1 (en) 1998-04-20 2005-12-08 Glycart Biotechnology Ag Antibody glycosylation variants having increased antibody-dependent cellular cytotoxicity
US20020006379A1 (en) 1998-06-22 2002-01-17 Hansen Hans J. Production and use of novel peptide-based agents for use with bi-specific antibodies
US6087362A (en) 1999-03-16 2000-07-11 Pentech Pharmaceuticals, Inc. Apomorphine and sildenafil composition
US20030004210A1 (en) 1999-11-24 2003-01-02 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US6436931B1 (en) 1999-11-24 2002-08-20 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US6706708B2 (en) 1999-11-24 2004-03-16 Immunogen, Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US6340701B1 (en) 1999-11-24 2002-01-22 Immunogen Inc Cytotoxic agents comprising taxanes and their therapeutic use
US20040087649A1 (en) 1999-11-24 2004-05-06 Immunogen Inc. Cytotoxic agents comprising taxanes and their therapeutic use
US20090087429A1 (en) 2000-03-21 2009-04-02 Jian Chen IL-17 homologous polypeptides and therapeutic uses thereof
US6333410B1 (en) 2000-08-18 2001-12-25 Immunogen, Inc. Process for the preparation and purification of thiol-containing maytansinoids
WO2002016602A2 (en) 2000-08-24 2002-02-28 Genentech, Inc. Compositions and methods for the diagnosis and treatment of tumor
JP2007077155A (ja) 2000-08-24 2007-03-29 Genentech Inc 腫瘍の診断と治療のための組成物と方法
US20030055226A1 (en) 2001-05-31 2003-03-20 Immunogen, Inc. Methods for preparation of cytotoxic conjugates of maytansinoids and cell binding agents
RU2321630C2 (ru) 2001-08-03 2008-04-10 Гликарт Биотекнолоджи АГ Гликозилированные антитела (варианты), обладающие повышенной антителозависимой клеточной цитотоксичностью
WO2003011878A2 (en) 2001-08-03 2003-02-13 Glycart Biotechnology Ag Antibody glycosylation variants having increased antibody-dependent cellular cytotoxicity
US6716821B2 (en) 2001-12-21 2004-04-06 Immunogen Inc. Cytotoxic agents bearing a reactive polyethylene glycol moiety, cytotoxic conjugates comprising polyethylene glycol linking groups, and methods of making and using the same
US20040002587A1 (en) * 2002-02-20 2004-01-01 Watkins Jeffry D. Fc region variants
US6756397B2 (en) 2002-04-05 2004-06-29 Immunogen, Inc. Prodrugs of CC-1065 analogs
US6534660B1 (en) 2002-04-05 2003-03-18 Immunogen, Inc. CC-1065 analog synthesis
US20040082764A1 (en) 2002-05-02 2004-04-29 Wyeth Holdings Corporation Calicheamicin derivative-carrier conjugates
US6596757B1 (en) 2002-05-14 2003-07-22 Immunogen Inc. Cytotoxic agents comprising polyethylene glycol-containing taxanes and their therapeutic use
US20040024049A1 (en) 2002-08-02 2004-02-05 Immunogen Inc. Cytotoxic agents containing novel potent taxanes and their therapeutic use
US20040126379A1 (en) 2002-08-21 2004-07-01 Boehringer Ingelheim International Gmbh Compositions and methods for treating cancer using cytotoxic CD44 antibody immunoconjugates and chemotherapeutic agents
US20060024298A1 (en) 2002-09-27 2006-02-02 Xencor, Inc. Optimized Fc variants
US20040241817A1 (en) 2003-01-22 2004-12-02 Glycart Biotechnology Ag Fusion constructs and use of same to produce antibodies with increased Fc receptor binding affinity and effector function
WO2004099379A2 (en) 2003-05-02 2004-11-18 Health Research, Inc. Use of jag2 expression in diagnosis of plasma cell disorders
US20040235840A1 (en) 2003-05-20 2004-11-25 Immunogen, Inc. Cytotoxic agents comprising new maytansinoids
US20050123549A1 (en) 2003-07-21 2005-06-09 Immunogen Inc. CA6 antigen-specific cytotoxic conjugate and methods of using the same
US20070148163A1 (en) 2003-12-25 2007-06-28 Kirin Beer Kabushiki Kaisha Mutants of anti-cd40 antibody
US20080171040A1 (en) 2004-06-01 2008-07-17 Genentech, Inc. Antibody-drug conjugates and methods
WO2006008548A2 (en) 2004-07-22 2006-01-26 Erasmus University Medical Centre Rotterdam Binding molecules
US20060045877A1 (en) * 2004-08-30 2006-03-02 Goldmakher Viktor S Immunoconjugates targeting syndecan-1 expressing cells and use thereof
US20070183971A1 (en) 2004-08-30 2007-08-09 Biotest Ag Immunoconjugates targeting syndecan-1 expressing cells and use thereof
CA2486285A1 (en) 2004-08-30 2006-02-28 Viktor S. Goldmakher Immunoconjugates targeting syndecan-1 expressing cells and use thereof
US20080063635A1 (en) 2004-09-22 2008-03-13 Kirin Beer Kabushiki Kaisha Stabilized Human Igg4 Antibodies
WO2006099875A1 (en) 2005-03-23 2006-09-28 Genmab A/S Antibodies against cd38 for treatment of multiple myeloma
US20090317391A1 (en) 2005-04-07 2009-12-24 Novartis Vaccines And Diagnostics Inc. Cancer Related Genes (PTPE)
WO2006110466A2 (en) 2005-04-07 2006-10-19 Novartis Vaccines And Diagnostics Inc. CANCER-RELATED GENES (PTPϵ)
JP2008535491A (ja) 2005-04-07 2008-09-04 ノバルティス ヴァクシンズ アンド ダイアグノスティクス, インコーポレイテッド 癌に関連した遺伝子(PTPε)
US20060233814A1 (en) 2005-04-15 2006-10-19 Immunogen Inc. Elimination of heterogeneous or mixed cell population in tumors
US20070054332A1 (en) 2005-08-10 2007-03-08 Alan Rapraeger Syndecan 1 ectodomain inhibits cancer
WO2007066109A1 (en) 2005-12-06 2007-06-14 Domantis Limited Bispecific ligands with binding specificity to cell surface targets and methods of use therefor
EP2006381A1 (en) 2006-03-31 2008-12-24 Chugai Seiyaku Kabushiki Kaisha Method for control of blood kinetics of antibody
WO2007144046A2 (de) 2006-05-03 2007-12-21 Elke Pogge Von Strandmann Mittel zur behandlung von malignen erkrankungen
US20100291105A1 (en) 2006-05-03 2010-11-18 Elke Pogge Von Strandmann Agent for the treatment of malignant diseases
US20090175863A1 (en) 2007-12-26 2009-07-09 Elmar Kraus Agents targeting cd138 and uses thereof
US20090181038A1 (en) 2007-12-26 2009-07-16 Gregor Schulz Method of decreasing cytotoxic side-effects and improving efficacy of immunoconjugates
US20090169570A1 (en) 2007-12-26 2009-07-02 Benjamin Daelken Methods and agents for improving targeting of cd138 expressing tumor cells
RU2010130993A (ru) 2007-12-26 2012-02-10 Биотест Аг (De) Способы улучшения направленного воздействия на cd138-экспрессирующие опухолевые клетки и агенты для их осуществления
US20110123554A1 (en) 2009-05-06 2011-05-26 Frank Osterroth Uses of immunoconjugates targeting cd138

Non-Patent Citations (118)

* Cited by examiner, † Cited by third party
Title
Aalberse et al., "The Apparent Monovalency of Human IgG4 is Due to Bispecificity," in Int Arch Allergy Immunol, vol. 118, 1999, pp. 187-189.
Akkina et al., "Modeling human lymphoid precursor cell gene therapy in the SCID-hu mouse," Blood, 1994, 84, pp. 1393-1398.
Anttonen et al., "High syndecan-1 expression is associated with favourable outcome in squamous cell lung Carcinoma treated with radical surgery," Lung Cancer, Jun. 2001, 32(3), pp. 297-305.
Barbareschi et al., "High syndecan-1 expression in breast Carcinoma is related to an aggressive phenotype and to poorer prognosis," Cancer, Aug. 1, 2003, 98(3), pp. 474-483.
Beatty et al., "Effect of Specific Antibody Pretreatment on Liver Uptake of (superscript)111In-labeled Anticarcinoembryonic Antigen Monoclonal Antibody in Nude Mice Bearing Human Colon Cancer Xenografts," Cancer Research, 1989,49, pp. 1587-1594.
Bendig M. M., Methods: A Companion to Methods in Enzymology, 1995; 8:83-93. *
Bernfield et al., "Biology of the syndecans: a family of transmembrane heparan sulfate proteoglycans," Annu RevCell Biol, 1992, 8, pp. 365-393.
Beste et al., "Small antibody-like proteins with prescribed ligand specificities derived from the lipocalin fold," Proc. Natl. Acad. Sei. USA, 1999, 96, pp. 1898-1903.
Bhattacharyy et al., "Maytansine binding to the vinblastine sites of tubulin," FEBS Lett, 1977, 75, pp. 159-162.
Blattler et al., "Drugs to Enhance the Therapeutic Potency of Anticancer Antibodies: Antibody-Drug Conjugates as Tumor-Activated Prodrugs," Anticancer Agents-Frontiers in Cancer Chemotherapy, American Chemical Society, Washington, DC, 2001, pp. 317-338.
Brekke et al., "Human IgG isotype-specific amino acid residues affecting complement-mediated cell lysis and phagocytosis", Eur. J. Immunol., 1994, vol. 24 No. 10, pp. 2542-2547.
Bross et al., "Approval summary: gemtuzumab ozogamicin in relapsed acute myeloid leukemia," Clin Cancer Res, 2001, 7, pp. 1490-1496.
Buchsbaum, "Experimental approaches to increase radiolabeled antibody localization in tumors," Cancer Research, 1995, 55, pp. 5729s-5732s.
Carbone et al., "AIDS-related plasma-blastic lymphomas of the oral cavity and jaws: a diagnostic dilemma," Ann. Otol. Rhinol. Laryngol., 1999, 108, pp. 95-99.
Carbone et al., "Reed-Sternberg cells of classical Hodgkin's disease react with the plasma cell-specific monoclonal antibody B-B4 and express human syndecan-1," Blood, 1997, 89, pp. 3787-3794.
Carter P., "Improving the efficacy of antibody-based Cancer therapies," Nat Rev Cancer, 2001, 1, pp. 118-129.
Casset et al. Biochemical and Biophysical Research Communications, 307:198-205, 2003. *
Chapman, "PEGylated antibodies and antibody fragments for improved therapy: a review," in Advanced Drug Delivery Reviews, vol. 54, 2002, pp. 531-545.
Chari et al., "Goldmacher vs. Enhancement of the selectivity and antitumor efficacy of a CC-1065 analogue through immunoconjugate formation," Cancer Res., 1995, 55, pp. 4079-4084.
Chari et al., "Goldmacher vs. Immunoconjugates containing novel maytansinoids: promising anticancerdrugs," Cancer Res., 1992, 52, pp. 127-131.
Charnaux et al., "Rantes (CCL5) induces a CCR5-dependent accelerated shedding of syndecan-1 (CD138) and syndecan-4 from HeLa cells and forms complexes with the shed ectodomains of these proteoglycans as well as with those of CD44," Glycobiology, 2005, 5(2) pp. 119-130.
Chen et al., "Engraftment of human hematopoietic precursor cells with secondary transfer potential in SCID-hu mice," Blood, 1994, 84, pp. 2497-2505.
Chilosi et al., "CD138/syndecan-1: a useful immunohistochemical marker of normal and neoplastic plasma cells on routine trephine bone marrow biopsies," Mod Pathol., 1999, 12 pp. 1101-1106.
Clement et al., "B-B2 and B-B4: two new mAb against secreting plasma cells," SFSe, ed. J. Leukocyte Typing V. Oxford: Oxford University Press, 1995 pp. 714-715.
Colman P. M. Research in Immunology, 145:33-36, 1994. *
Cortesini: "Pancreas cancer and the role of soluble immunoglobulin-like transcript 3 (ILT3)," in JOP: Journal Of The Pancreas 2007, vol. 8, No. 6, Nov. 1, 2007, pp. 697-703.
Couturier et al., "Validation of 213Bi-alpha radioimmunotherapy for multiple myeloma," Clinical Cancer Research, 5(10 Suppl.), Oct. 1999, pp. 3165s-3170s.
Davies et al., "Distribution and Clinical Significance of Heparan Sulfate Proteoglycans," Ovarian Cancer Clin Cancer Res., 2004, 10(15), pp. 5178-5186.
Devita et al., "Biological methods of treating oncological diseases," in Medicine, Moscow edition, 2002, pp. 538.
Dhodapkar et al., "Antitumor monoclonal abs enhance cross-presentation of Cellular antigens and the generation of myeloma-specific killer T cells by dendritic cells," J Exp Med, Jan. 7, 2002, 195(1), pp. 125-133.
Dhodapkar et al., "Syndecan-1 is a multifunctional regulator of myeloma pathobiology: control of tumor cell survival, growth, and bone cell differentiation," Blood, 1998, 91, pp. 2679-2688.
Dhodapkar et al., "T cells from the tumor microenvironment of patients with progressive myeloma can generate strong, tumor-specific cytolytic responses to autologous, tumor-loaded dendritic cells," Proc Natl Acad Sci U S A., Oct. 1, 2002, 99(20) pp. 13009-13013, Epub Sep. 16, 2002.
Dore et al., "Identification and location on syndecan-1 core protein of the epitopes of B-B2 and B-B4 monoclonal antibodies," FEBS Lett., 1998, 426, pp. 67-70.
Dowell et al., "Pharmacokinetics of gemtuzumab ozogamicin, an antibody-targeted chemotherapy agent for the treatment of patients with acute myeloid leukemia in first relapse," J Clin Pharmacol, 2001, 41, pp. 1206-1214.
E. G. Matveeva et al., "Synthesis ofthe phthalocyanines conjugates with monoclonal antibodies in the medium of reversed micelles AOt/octane andin an aqueous-organic mixture", Bioorganic Chemistry, 1998, vol. 24, N1, pp. 64-71.
Edinger et al., "Noninvasive assessment of tumor cell proliferation in animal models," Neoplasia, 1999, 1, pp. 303-310.
Fundamental Immunology, (William E. Paul, M.D. ed., 3d ed. 1993), p. 242. *
Fundamental Immunology, William E. Paul M.D., ed., 3rd Ed., pp. 292-295, 1993. *
Gattei et al., "Characterization of Anti-CD138 monoclonal antibodies as tools for investigating the molecular polymorphism of syndecan-1 in human lymphoma cells," Br J Haematol, 1999, 104, pp. 152-162.
Hamann et al., "An anti-CD33 antibody-calicheamicin conjugate for treatment of acute myeloid leukemia. Choice of linker," Bioconjug Chem, 2002, 13, pp. 40-46.
Hamilton, "Molecular engineering; applications to clinical laboratory," Clin. Chem., 1993, 39(9), pp. 1988-1997.
Han et al., "New insights into syndecan-2 expression and tumourigenic activity in colon carcinoma cells," J Mol Histol., 2004, 35(3), pp. 319-326.
Horvathova et al., "Identification of novel and specific antigens of human plasma cells by mAb," SFSe, ed. Leucocyte Typing V. Oxford: Oxford University Press, 1995, pp. 713-714.
Hwang et al., "Immunogenicity of engineered antibodies," Methods, 2005, 36(1), pp. 3-10.
Israel et al.: "Plasmapheresis and inmunological control of cancer," in Lancet Sep. 18, 1976, vol. 2, No. 7986, pp. 642-643.
Jokimaa et al., "Expression of syndecan-1 in human placenta and decidua," Placenta, Mar.-Apr. 1998, 19(2-3), pp. 157-163.
Jokimaa et al., "Placental expression of syndecan 1 is diminished in preeclampsia," Am J Obstet Gynecol, Dec. 2000, 183(6), pp. 1495-1498.
Kipriyanov et al., "Generation and production of engineered antibodies," Mol. Biotechnol., 2004, 26(1), pp. 39-60.
Krebs et al., "High-throughput generation and engineering of recombinant human antibodies," J. Immunol, Methods 254, 2001, pp. 67-84.
Kupchan et al., "Structural requirements for antileukemic activity among the naturally occurring and semisynthetic maytansinoids," J Med Chem, 1978, 21, pp. 31-37.
Kyoizumi et al., "Implantation and maintenance of functional human bone marrow in SCID-hu mice," Blood, 1992, 79, pp. 1704-1711.
Kyoizumi et al., "Preclinical analysis of cytokine therapy in the SCID-hu mouse," Blood, 1993, 81 pp. 1479-1488.
Liu et al., "Eradication of large colon tumor xenografts by targeted delivery of maytansinoids," Proc Natl Acad Sci U S A, 1996, 93, pp. 8618-8623.
MacCallum et al. J. Mol. Biol., 262, 732-745, 1996. *
McCune et al., "The SCID-hu mouse: murine model for the analysis of human hematolymphoid differentiation and function," Science, 1988, 241, pp. 1632-1639.
Mennerich et al. "Shift of syndecan-1 expression from epithelial to stromal cells during progression of solid tumours," Eur J Cancer, Jun. 2004, 40(9), pp. 1373-1382.
Mosmann T., "Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays," J Immunol Methods, 1983, 65, pp. 55-63.
Mukunyadzi et al., "The level of syndecan-1 expression is a distinguishing feature in behavior between keratoacanthoma and invasive cutaneous squamous cell carcinoma," Mod Pathol., Jan. 2002, 15(1), pp. 45-49.
Namikawa et al., "Growth of human myeloid leukemias in the human marrow environment of SCID-hu mice," Blood, Oct. 15, 1993, 82(8), pp. 2526-2536.
O'Connell FP et al., "CD138 (Syndecan-1), a Plasma Cell Marker Immunohistochemical Profile in Hematopoietic and Nonhematopoietic Neoplasms," Am J Clin Pathol, 2004, 121, pp. 254-263.
Office Action issued by the Russian Patent Office an Dec. 5, 2013 in Russian application No. 201030977.
Ojima et al., "Tumor-specific novel taxoid-monoclonal antibody conjugates," 2002, J. Med. Chem., 45, pp. 5620-5623.
Olafsen et al., "Covalent disulfide-linked anti-CEA diabody allows site-specific conjugation and radiolabeling for tumor targeting applications," 2004, Prot. Eng. Design & Selection, 17, 1, pp. 21-27.
Orosz et al., "Syndecan-1 expression in different soft tissue tumours," Anticancer Res., 2001, 21(1B), pp. 733-737.
Padlan, EA, "A possible procedure for reducing the immunogenicity of antibody variable domains while preserving their ligand-binding properties," Mol. Immunol., 1991, 28 pp. 489-498.
Palacios et al., "B-B4 monoclonal antibody and identification of human bone marrow plasma cells (including response)," Br J Haematol, 1997, 96, pp. 654-657.
Payne G., "Progress in immunoconjugate cancer therapeutics," Cancer Cell, 2003, 3, pp. 207-212.
Pegram et al. "Phase II study of receptor-enhanced chemosensitivity using recombinant humanized anti-p185HER2/neu monoclonal antibody plus cisplatin in patients with HER2/neu-overexpressing metastatic breast cancer refractory to chemotherapy treatment," 1998, J. Clin. Oncol., 16, pp. 2659-2671.
Post et al., "Efficacy of an anti-CD138 immunotoxin and doxorubicin on drug-resistant and drug-sensitive myeloma cells," Int J Cancer, Nov. 12, 1999, 83(4), pp. 571-576.
Rawstron et al., "Circulating plasma cells in multiple myeloma: characterization and correlation with disease stage," Br J Haematol, 1997, 97, pp. 46-55.
Reichert, "Marketed Therapeutic Antibodies Compendium," in mAbs, 4:3, May/Jun. 2012, pp. 413-415.
Remillard et al., "Antimitotic activity of the potent tumor inhibitor maytansine," Science, 1975,189, pp. 1002-1005.
Rintala et al., "Association of syndecan-1 with tumor grade and histology in primary invasive cervical carcinoma," Gynecol Oncol, Dec. 1999, 75(3), pp. 372-378.
Roguska et al., "Humanization of murine monoclonal antibodies through variable domain resurfacing," Proc Natl Acad Sci U S A, 1994, 91, pp. 969-973.
Roitt et al, Immunology Illustrated (original book 5th Edition), Nankodo, Feb. 10, 2000, 1st Edition, pp: 77-78.
Ross et al., "Anticancer Antibodies," Am J Clin Path, 2003, 119, pp. 472-485.
Ross et al., "Prostate stem cell antigen as therapy target: tissue expression and in vivo efficacy of an immunoconjugate," Cancer Res, May 1, 2002, 62(9), pp. 2546-2553.
Rudikoff et al. Proc. Natl. Acad. Sci. USA, 79(6):1979-1983, Mar. 1982. *
Rudikoff et al., "Single amino acid substitution altering antigen-binding specificity," PNAS, 1982, 79(6), pp. 1979-1983.
Sanderson et al., "B lymphocytes express and lose syndecan at specific stages of differentiation," Cell Regul, 1989, 1, pp. 27-35.
Sandhu et al., "Human hematopoiesis in SCID mice implanted with human adult cancellous bone," Blood, 1996, 88, pp. 1973-1982.
Sasaki et al., "Bisphosphonate risedronate reduces metastatic human breast cancer burden in bone in nude mice," Cancer Res, 1995, 55, pp. 3551-3557.
Schneider et al., "Two subsets of peripheral blood plasma cells defined by differential expression of CD45 antigen," Br J Haematol, 1997, 97, pp. 56-64.
Sebestyen et al., "Syndecan-1 (CD138) expression in human non-Hodgkin lymphomas," Br J Haematol, 1999, 104(2), pp. 412-419.
Seftalioglu et al., "Syndecan-1 (CD138) expression in acute myeloblastic leukemia cells-an immuno electron microscopic study," Acta Oncol, 2003, 42, pp. 71-74.
Seftalioglu et al., "Syndecan-1/CD138 expression in normal myeloid, acute lymphoblastic and myeloblastic leukemia cells," Acta Histochem, 2003, 105, pp. 213-221.
Senter et al., "Cures and regressions of established tumors with monoclonal antibody auristatin conjugates," Abstract #2062, Proc. Am. Assoc. Can. Res. (San Francisco, CA: American Association for Cancer Res.), Mar. 2002, 43 pp. 414-415.
Sharkey Robert M et al: "Targeted therapy of Cancer: new prospects for antibodies and immunoconjugates." in CA: A Cancer Journal For Clinicians Jul.-Aug. 2006, vol. 56, No. 4, 2006-07, pp. 226-243.
Sievers et al., "Efficacy and safety of gemtuzumab ozogamicin in patients with CD33-positive acute myeloid leukemia in first relapse," J. Clin. Oncol, 2001, 19, pp. 3244-3254.
Sievers et al., "Mylotarg: antibody-targeted chemotherapy comes of age," Curr. Opin. Oncol., 2001, 13, pp. 522-527.
Smith R., Single chain antibody variable region fragments; www.stanford.edu/~smithr/science/scfv.html (last updated in May 2001).
Smith R., Single chain antibody variable region fragments; www.stanford.edu/˜smithr/science/scfv.html (last updated in May 2001).
Stanley et al., "Syndecan-1 expression is induced in the stroma of infiltrating breast carcinoma," Am J Clin Pathol., Sep. 1999, 112(3), pp. 377-383.
Studnicka et al. "Human-engineered monoclonal antibodies retain full specific binding activity by preserving non-CDR complementarity-modulating residues," Protein Eng., 1994, 7(6), pp. 805-814.
Sun et al., "Large scale and clinical grade purification of syndecan-1+ malignant plasma cells," J Immunol Methods, Jun. 23, 1997, 205(1), pp. 73-79.
Supiot et al., "Compariosn of the Biologic Effects of MA5 and B-B4 Monoclonal Antibody Labeled with Iodine-131 and Bismuth-213 on Multiple Myeloma," Cancer, vol. 94, No. S4, pp. 1202-1209.
Tassone et al, Blood, Nov. 16, 2003, vol. 102, 45th ASH meeting abstract 449s-450a (abstract).
Tassone et al., "Cytotoxic activity of the maytansinoid immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells," Blood Journal, vol. 104 (12), Dec. 1, 2004, pp. 3688-3696.
Tassone et al., "In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2′-Deacetyl-N2′-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells," Cancer Research, vol. 64, Jul. 1, 2004, pp. 4629-4636.
Tassone et al., "In vitro and in vivo activity of the maytansinoid immunoconjugate huN901-N2'-Deacetyl-N2'-(3-Mercapto-1-Oxopropyl)-Maytansine against CD56+ Multiple Myeloma Cells," Cancer Research, vol. 64, Jul. 1, 2004, pp. 4629-4636.
Tassone et al., Proc Amer Assoc Cancer Res, vol. 45, abstract#1425, Mar. 2004, abstract.
Tassone Pierfrancesco et al: "Cytotoxic activity of the nriaytansinoid Immunoconjugate B-B4-DM1 against CD138+ multiple myeloma cells." in Blood Dec. 1, 2004, vol. 104, No. 12, Dec. 1, 2004, pp. 3688-3696.
Tolcher et al., "Cantuzumab mertansine, a maytansinoid immunoconjugate directed to the CanAg antigen: a phase I, pharmacokinetic, and biologic correlative study," J Clin Oncol, 2003, 21, pp. 211-222.
Turner et al.: "1311-Anti CD20 radioimmunotherapy of relapsed or refractory non-Hodgkins lymphoma: a phase II clim'cal trial of a nonmyeloablative dose regimen of chimeric rituximab radiolabeled in a hospital," in Cancer Biotherapy & Radiopharmaceuticals Aug. 2003, vol. 18, No. 4, 2003-08, pp. 513-524.
Urashima et al., "The development of a model for the homing of multiple myeloma cells to human bone marrow," Blood, 1997, 90, pp. 754-765.
Vogel, CW, "Preparation of immunoconjugates using antibody oligosaccharide moieties. Methods in Molecular Biology: Bioconjugation protocols strategies and methods," 2004, 283, pp. 87-108.
Vooijs et al., "Efficacy and toxicity of plasma-cell-reactive monoclonal antibodies B-B2 and B-B4 and their immunotoxins," Cancer Immunol Immunother, 1996, 42, pp. 319-328.
Ward et al. "Binding activities of a repertoire of single immunoglobin variable domains secreted from Escherichia coli," Nature, 1989, 341, pp. 544-546.
Wargalla et al., "Rate of internalization of an immunotoxin correlates with cytotoxic activity against human tumor cells," Proc. Natl. Acad. Sci. USA, 1989, 86, pp. 5146-5150.
Wijdenes et al. "A plasmocyte selective monoclonal antibody (B-B4) recognizes syndecan-1," Br J Haematol, 1996, 94, pp. 318-323.
Wijdenes et al., "CD138" J Biol Regul Homeost Agents, Apr.-Jun. 2002, 16(2), pp. 152-155.
Wiksten et al. ''Epithelial and stromal syndecan-1 expression as predictor of outcome in patients with gastric cancer," Int J Cancer," Jan. 20, 2001, 95(1), pp. 1-6.
Winter et al., "Human antibodies," Immunology Today, Jun. 1993, 14(6), pp. 243-246.
Witzig et al., "Detection of myeloma cells in the peripheral blood by flow cytometry," Cytometry, 1996, 26, pp. 113-120.
Wu et al., "Humanization of a murine monoclonal antibody by simultaneous optimization of framework and CDR residues," JMB, 1999, 294, pp. 151-162.
Xie et al., "Pharmacokinetics and biodistribution of the antitumor immunoconjugate, cantuzumab mertansine (huC242- DM1), and its two components in mice," J Pharmacol Exp Ther, Mar. 2004, 308(3), pp. 1073-1082.
Yang et al., "Genetically fluorescent melanoma bone and organ metastasis models," Clin Cancer Res, 1999, 5, pp. 3549-3559.
Yang et al., "Whole-body optical imaging of green fluorescent protein-expressing tumors and metastases," Proc Natl Acad Sci U S A, 2000, 97, pp. 1206-1211.

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